Striatal DAT Research Articles

Correlation between longitudinal changes of clinical symptoms and striatal DAT uptake in DLB

AbstractBackgroundIt is widely known that there is low striatal 123I‐FP‐CIT dopamine transporter single photon emission tomography (DaT‐SPECT) uptake in patients with dementia with Lewy bodies (DLB). There are no study about the association between longitudinal changes of clinical sign and DaT‐uptake in Parkinson syndrome, especially in DLB. The aim of this study is to investigate the association between the longitudinal changes of DaT uptake and severity of parkinsonism and cognitive funtion in DLB.MethodA total of 35 outpatients with probable DLB who underwent DaT‐SPECT twice (initial and follow up period) from the Memory Disorder Clinic at the Department of Geriatric Medicine, Tokyo Medical University, were enrolled in this study from April 2014 until September 2020. We examined the correlation between annual changes of DaT uptake and symptoms (cognitive function decline, parkinsonism) in the patients with DLB.ResultThere was significant correlation between annual changes of severity of parkinsonism and DAT uptake in left posterior putamen (r = ‐0.39, p = 0.03), MMSE scores and DaT uptake in the entire regions except right posterior putamen (P< 0.05) in patients with DLB.ConclusionThese results may suggest clarifying the mechanism of dysfunction of nigrostriatal projection pathway in DLB.

Utility of Baseline Pathological, Neuroimaging and Clinical Markers for Progression Prognosis and Subtype Classification in Early Parkinson’s Disease: Implications for Cognitive Impairment

AbstractBackgroundCognitive dysfunction is a well‐recognised PD symptom, but it is highly heterogenous and under‐assessed clinically. Interestingly, PD motor subtypes are associated with different risk of cognitive decline. However, subtype classification is currently reliant on subjective clinician assessment and may consequently be misdiagnosed. Therefore, objective biomarkers of PD progression are critically needed, but must be validated prior to clinical deployment. We assessed the utility of various clinical, neuroimaging and pathological measures as predictors of cognitive outcomes up to 5‐years follow‐up in early PD.MethodData was extracted from the Parkinson’s Progression Markers Initiative. Cognitive assessments were compiled into an overall cognition score via principal component analysis. Distinct subgroups were identified via Fuzzy C‐Means clustering on Year‐5 Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores. Models predicting cluster membership were created via logistic regression and a stratified cross‐validation machine learning pipeline, comparing two predictor inputs: 1) baseline motor assessments; and 2) incorporating additional measures, including prodromal assessments (sleep, olfactory and autonomic function), neuroimaging (proxy SN volume, striatal DaT binding) and biofluid markers (CSF alpha‐syn, p‐tau, a‐beta, and serum IGF‐1) at baseline. Finally, cluster membership was used for retroactive assessment of baseline and follow‐up cognitive data.ResultsTwo clusters were identified, with cluster two (n = 117) demonstrating higher rigidity, lower DaT binding, worsened motor outcomes and increased mood dysfunction at follow‐up compared to tremor‐dominant cluster one (n = 183). Additionally, rigid‐dominant membership was predicted by male sex, higher p‐tau, along with lower a‐beta, predicting 40% of variance (n = 111). This was significantly higher (P<0.001) than baseline motor scores alone, only accounting for 18% of variance. This was supported by machine learning, whereby incorporating additional assessments corresponded to a classification accuracy of 62%, compared to 26% when omitted. Finally, higher probability of belonging to the rigid‐dominant cluster yielded significant negative correlations cognition at baseline and follow‐up.ConclusionIncreased likelihood of rigid‐dominance corresponded to more profound cognitive decline, which may in part result from neuropathological marker concentrations as highlighted by predictive models. Therefore, further tracking of this cohort, specifically conversion into MCI or dementia, could provide insight into pathological contribution to differences in cognitive decline between PD subtypes.

In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease

Direct targeting of alpha-synuclein (ASYN) has emerged as a disease-modifying strategy for Parkinson’s disease and other synucleinopathies which is being approached using both small molecule compounds and ASYN-targeted biologics. Minzasolmin (UCB0599) is an orally bioavailable and brain-penetrant small molecule ASYN misfolding inhibitor in clinical development as a disease-modifying therapeutic for Parkinson’s disease. Herein the results of preclinical evaluations of minzasolmin that formed the basis for subsequent clinical development are described. Pharmacokinetic evaluations of intraperitoneal 1 and 5 mg/kg minzasolmin in wildtype mice revealed parallel and dose-proportional exposures in brain and plasma. Three-month administration studies in the Line 61 transgenic mouse model of PD were conducted to measure ASYN pathology and other PD-relevant endpoints including markers of CNS inflammation, striatal DAT labeling and gait. Reductions in ASYN pathology were correlated with improved aspects of gait and balance, reductions in CNS inflammation marker abundance, and normalized striatal DAT levels. These findings provide support for human dose determinations and have informed the translational strategy for clinical trial design and biomarker selection for the ongoing clinical studies of minzasolmin in patients living with early-stage Parkinson’s disease (ClinicalTrials.gov ID: NCT04658186; EudraCT Number 2020–003265).

LRRK2 and GBA1 variant carriers have higher urinary bis(monacylglycerol) phosphate concentrations in PPMI cohorts

We quantified concentrations of three isoforms of the endolysosomal lipid, bis(monoacylglycerol) phosphate (BMP) in the urine of deeply phenotyped cohorts in the Parkinson’s Progression Markers Initiative: LRRK2 G2019S PD (N = 134) and non-manifesting carriers (NMC) (G2019S+ NMC; N = 182), LRRK2 R1441G PD (N = 15) and R1441G+ NMC (N = 15), GBA1 N409S PD (N = 76) and N409S+ NMC (N = 178), sporadic PD (sPD, N = 379) and healthy controls (HC) (N = 190). The effects of each mutation and disease status were analyzed using nonparametric methods. Longitudinal changes in BMP levels were analyzed using linear mixed models. At baseline, all LRRK2 carriers had 3–7× higher BMP levels compared to HC, irrespective of the disease status. GBA1 N409S carriers also showed significant, albeit smaller, elevation (~30–40%) in BMP levels compared to HC. In LRRK2 G2019S PD, urinary BMP levels remained stable over two years. Furthermore, baseline BMP levels did not predict disease progression as measured by striatal DaT imaging, MDS-UPDRS III Off, or MoCA in any of the cohorts. These data support the utility of BMP as a target modulation biomarker in therapeutic trials of genetic and sPD but not as a prognostic or disease progression biomarker.

Evolution characteristics of dynamic balance disorder over the course of PD and relationship with dopamine depletion.

This study aimed to assess the evolution of dynamic balance impairment during the course of Parkinson's disease (PD) and to clarify the contribution of striatal dopaminergic innervation to poor dynamic balance. In our study, 89 patients with PD (divided into 2 groups according to the H-Y stage) and 39 controls were included. Kinematic data were recorded by a portable inertial measurement unit system. Dopaminergic loss in the striatal subregion was verified through the 11C-CFT PET examination. The severity of white matter hyperintensities (WMHs) was assessed by the Scheltens scale. The correlation between dynamic kinematic parameters and dopamine transporter availability was analyzed by multivariate regression analysis. Patients with early PD presented with imbalance featured by smaller three-dimensional trunk ROM with reduced trunk coronal angular velocity during walking and with reduced trunk sagittal angular velocity during the stand-to-sit task (all p < 0.05). These abnormalities were not more severe at a later stage. The ROM in the coronal and transverse planes during walking correlated with caudate DAT uptake (β = 0.832, p = 0.006, Q = 0.030, and β = 0.890, p = 0.003, Q = 0.030) after controlling for age, gender, and WMHs. As the disease progressed, the trunk sagittal and transverse angular velocities during walking and trunk sagittal angular velocity when turning and sitting-to-standing were slower, which was accompanied by reduced gait velocity gradually (all p < 0.05). These parameters related to disease progression have no association with striatal DAT uptake (all p > 0.05). The dynamic balance in PD was impaired from the early stages, and the characteristics of the impairment changed differently as the disease progressed. Dopaminergic denervation has a lower contribution to dynamic balance disorders throughout PD.

Longitudinal DAT changes measured with [18F]FE-PE2I PET in patients with Parkinson’s disease; a validation study

BackgroundDopamine transporter (DAT) PET provides higher resolution than DAT SPECT and opportunity for integrated imaging with MRI. The radioligand [18F]FE-PE2I is highly selective for the DAT, and PET measurements with this radioligand have good reliability and repeatability in patients with non-advanced Parkinson’s disease. ObjectivesTo validate [18F]FE-PE2I PET as measurement tool of longitudinal DAT changes in patients with Parkinson’s disease. MethodsThirty-seven subjects with Parkinson’s disease (Hoehn and Yahr stage < 3) were included in a longitudinal PET study with [18F]FE-PE2I. DAT availability (BPND) in the caudate nucleus, putamen, sensorimotor striatum, and substantia nigra, was estimated with parametric imaging using Logan graphical analysis and cerebellum as reference region. For comparison with DAT-SPECT literature, sample size calculations for disease intervention studies were made. ResultsBaseline and follow-up PET data (interval: 2.3 ± 0.5 years) were available for 25 patients (9 females, 16 males). Median age was 64.7 years (range 46–76); symptom duration: 3 years (0.25–14); Hoehn and Yahr stage (H&Y): 1 (1–2). Annualized DAT decline and effect size were: −8.5 ± 6.6 % and 1.08 for caudate nucleus; −7.1 ± 6.1 % and 1.02 for putamen; −8.3 ± 8.5 % and 0.99 for sensorimotor striatum; −0.11 ± 9.3 % and 0.11 for substantia nigra. The estimated minimum sample size needed for a treatment trial using [18F]FE-PE2I PET as imaging marker is 2–3 times lower than is reported in literature on [123I]FP-CIT SPECT. ConclusionsLongitudinal [18F]FE-PE2I PET measurements in non-advanced PD demonstrate a striatal DAT decline consistent with previous SPECT and PET studies. No obvious changes of DAT availability were observed in the substantia nigra, indicating perhaps slower progression or compensatory changes. The effect sizes were numerically larger than reported in the literature for other DAT radioligands, suggesting that [18F]FE-PE2I might detect smaller DAT changes, and can be well used as progression marker in clinical trials.

Predicting the onset of freezing of gait in Parkinson’s disease

BackgroundFreezing of gait is a debilitating symptom of Parkinson’s disease associated with high risks of falls and poor quality of life. While productive therapy for FoG is still underway, early prediction of FoG could help high-risk PD patients to take preventive measures. In this study, we predicted the onset of FoG in de novo PD patients using a battery of risk factors from patients enrolled in PPMI cohort.MethodsBaseline characteristics were compared between subjects who developed FoG (68 patients, 37.2%, pre-FoG group) during the five-year follow up and subjects who did not (115 patients, 62.8%, non-FoG group). A multivariate logistic regression model was built based on backward stepwise selection of factors that were associated with FoG onset in the univariate analysis. ROC curves were used to assess sensitivity and specificity of the predictive model.ResultsAt baseline, age, PIGD score, cognitive functions, autonomic functions, sleep behavior, fatigue and striatal DAT uptake were significantly different in the pre-FoG group relative to the non-FoG group. However, there was no difference in genetic characteristics between the two patient sets. Univariate analysis showed several motor and non-motor factors that correlated with FoG, including PIGD score, MDS-UPDRS part II score, SDMT score, HVLT Immediate/Total Recall, MOCA, Epworth Sleepiness Scale, fatigue, SCOPA-AUT gastrointestinal score, SCOPA-AUT urinary score and CSF biomarker Abeta42. Multivariate logistic analysis stressed that high PIGD score, fatigue, worse SDMT performance and low levels of Abeta42 were independent risk factors for FoG onset in PD patients.ConclusionsCombining motor and non-motor features including PIGD score, poor cognitive functions and CSF Abeta can identify PD patients with high risk of FoG onset.

Sensor-based gait analysis in the premotor stage of LRRK2 G2019S-associated Parkinson's disease

IntroductionThere is a need for biomarkers to monitor the earliest phases of Parkinson's disease (PD), especially in premotor stages. Here, we studied whether there are early gait alterations in carriers of the G2019S mutation of LRRK2 that can be detected by means of an inertial sensor system. MethodsTwenty-one idiopathic PD patients, 20 LRRK2-G2019S PD, 27 asymptomatic carriers of LRRK2-G2019S mutation (AsG2019S) and 36 controls walked equipped with 16 lightweight inertial sensors in three different experiments: i/normal gait, ii/fast gait and iii/dual-task gait. In the AsG2019S group, DaT-SPECT (123I-ioflupane) with semi-quantitative analysis was carried out. Motor and cognitive performance were evaluated using MDS-UPDRS-III and MoCA scales. We employed neural network techniques to classify individuals based on their walking patterns. ResultsPD patients and controls showed differences in speed, stride length and arm swing amplitude, variability and asymmetry in all three tasks (p < 0.01). In the AsG2019S group, the only differences were detected during fast walking, with greater step time on the non-dominant side (p < 0.05), lower step/stride time variability (p < 0.01) and lower step time asymmetry (p < 0.01). DaT uptake showed a significant correlation with step time during fast walking on the non-dominant side (r = −0.52; p < 0.01). The neural network was able to differentiate between AsG2019S and healthy controls with an accuracy rate of 82.5%. ConclusionOur sensor-based analysis did not detect substantial and robust changes in the gait of LRRK2-G2019S asymptomatic mutation carriers. Nonetheless, step or stride time during fast walking, supported by the observed correlation with striatal DaT binding deserves consideration as a potential biomarker in future studies.

Pathophysiology and Symptomatology of Drooling in Parkinson's Disease.

Drooling can present in patients with Parkinson’s disease (PD), and it is manifested as an excessive pooling of saliva inside the oral cavity. Currently, the exact pathophysiological mechanism of drooling in PD is not yet fully explicated. Thus, it becomes crucial to understand if some clinical characteristics may emphasize drooling or if they are just concomitant. In PD, excessive drooling has been associated with a higher burden of non-motor symptoms, such as cognitive impairment, sleep problems, autonomic dysfunction, constipation and orthostatic hypotension, and of worse severity of motor fluctuations and bradykinesia. PD patients with excessive drooling also showed a reduction of striatal DAT availability at DaTSCAN imaging. Excessive drooling in patients with Parkinson’s cannot be attributed to a single factor but to a mixture of factors, including but not limited to impaired nigrostriatal pathways.

The impact of probable rapid eye movement sleep behavior disorder on Parkinson's disease: A dual-tracer PET imaging study

ObjectiveWith a dual-tracer PET study design, this study aimed to identify the differences between PD patients with and without probable RBD (PD+RBD+/PD+RBD-) and the influence of timing of RBD onset [probable RBD anterior to PD onset (PD+RBDa)/probable RBD posterior to PD onset (PD+RBDp)]. MethodsSeventy-four PD+RBD+ patients, sixty-three PD+RBD-patients and twenty healthy controls were enrolled. Clinical variates, striatal DAT tracer uptake, voxel-wise glucose metabolism and Parkinson's disease-related pattern (PDRP) expressions were compared among groups. ResultsNo significant difference were found on clinical characteristics between PD+RBD+ and PD+RBD-groups. Compared with PD+RBD-group, PD+RBD+ group had more severe dopaminergic dysfunction (p<0.05) except for posterior putamen in the more affected hemisphere (MAH) (p = 0.350). Meanwhile, it showed relative hypermetabolism in anterior putamen in the less affected hemisphere (LAH), bilateral anterior pallidum with wider involvement in the LAH, hippocampus and para-hippocampus in the LAH and bilateral olfactory gyrus, together with relative hypometabolism in limited bilateral posterio-parietal area (p<0.001). Significantly elevated PDRP expression was also seen in PD+RBD+ group (p < 0.01). For the timing of RBD onset, PD+RBDa patients harbored greater progression rate than PD+RBDp patients (p<0.01), greater DAT declining rates of striatal subregions and greater increasing rate of PDRP expressions than both PD+RBDp and PD+RBD-patients (p<0.05). ConclusionOur study found that PD patients with probable RBD have worse striatal dopaminergic dysfunction and higher PDRP network activity, supporting the assumption that PD with RBD may be a specific phenotype of PD. Additionally, RBD preceding PD onset may indicate a steeper disease decline.

Serial DaT-SPECT imaging in asymptomatic carriers of LRRK2 G2019S mutation: 8 years' follow-up.

Carriers of the G2019S mutation of LRRK2 provide a great opportunity to investigate the premotor stages of Parkinson's disease (PD). We have studied by serial clinical and dopamine transporter single photon emission computed tomography (DaT-SPECT) evaluations a cohort of asymptomatic carriers of the LRRK2-G2019S mutation in order to evaluate the usefulness of these tools as biomarkers. Here we report the results of the extended follow-up of this cohort at 8years. Seventeen participants, of the 25 available from the 4-year evaluation, completed the 8-year assessment. UPDRS-III, UPSIT test and DaT-SPECT imaging (123 I-ioflupane) were performed. We used repeated-measures linear mixed effects models to examine the changes in DaT binding over time. Three carriers had converted to PD at 4 years. One additional carrier converted at 8 years. PD-converters had lower striatal DaT binding at baseline than non-converters. There was a significant decline of DaT binding over time, with a mean annual rate of 3.5%, with somewhat inter-individual and intra-individual variability and comparable between PD-converters and non-converters. No carrier with DAT binding ratio above an undefined threshold between 0.5 and 0.8 developed PD symptoms. The age-adjusted UPSIT score did not change significantly over time. The rate of conversion to PD at 8years in this cohort aged ~58years at baseline was 16%. The observed decline of DaT binding over time and its association with the phenotype render DaT-SPECT a potentially useful tool for monitoring the premotor stage of the disease, although at the individual level its ability to predict phenoconversion is limited.

Sex-dependent alterations in behavior, drug responses and dopamine transporter expression in heterozygous DAT-Cre mice

Heterozygous mice that express Cre-recombinase under the dopamine transporter promoter (DAT-Cre knock in mice, or KI) are widely used for targeting midbrain dopamine neurons, under the assumption that their constitutive physiology is not affected. We report here that these mice display striking sex-dependent behavioral and molecular differences in relation to wildtypes (WT). Male and female KI mice were constitutively hyperactive, and male KI mice showed attenuated hyperlocomotor responses to amphetamine. In contrast, female KIs displayed a marked reduction in locomotion (“calming” effect) in response to the same dose of amphetamine. Furthermore, male and female DAT-Cre KI mice showed opposing differences in reinforcement learning, with females showing faster conditioning and males showing slower extinction. Other behavioral variables, including working memory and novelty preference, were not changed compared to WT. These effects were paralleled by differences in striatal DAT expression that disproportionately affected female KI mice. Our findings reveal clear limitations of the DAT-Cre line that must be considered when using this model.

Altered striatal dopamine levels in Parkinson\u2019s disease VPS35 D620N mutant transgenic aged mice

Vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans-Golgi network. Mutations such as D620N in the VPS35 gene have been identified in patients with autosomal dominant Parkinson’s disease (PD). However, it remains poorly understood whether and how VPS35 deficiency or mutation contributes to PD pathogenesis; specifically, the studies that have examined VPS35 thus far have differed in results and methodologies. We generated a VPS35 D620N mouse model using a Rosa26-based transgene expression platform to allow expression in a spatial manner, so as to better address these discrepancies. Here, aged (20-months-old) mice were first subjected to behavioral tests. Subsequently, DAB staining analysis of substantia nigra (SN) dopaminergic neurons with the marker for tyrosine hydroxylase (TH) was performed. Next, HPLC was used to determine dopamine levels, along with levels of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum. Western blotting was also performed to study the levels of key proteins associated with PD. Lastly, autoradiography (ARG) evaluation of [3H]FE-PE2I binding to the striatal dopamine transporter DAT was carried out. We found that VPS35 D620N Tg mice displayed a significantly higher dopamine level than NTg counterparts. All results were then compared with that of current VPS35 studies to shed light on the disease pathogenesis. Our model allows future studies to explicitly control spatial expression of the transgene which would generate a more reliable PD phenotype.

Longitudinal evolution of non-motor symptoms according to age at onset in early Parkinson's disease

ObjectiveTo investigate the longitudinal change of non-motor symptoms according to the age at onset in Parkinson's disease (PD). MethodsThis cohort study using the Parkinson's Progression Markers Initiative data included 405 patients with early PD. They were classified into late-onset (age at onset ≥ 70 years, n = 63), middle-onset (50 to 69 years, n = 268), and young-onset (<50 years, n = 74) groups. Non-motor symptoms were assessed with well-validated instruments covering neuropsychiatric, sleep-related, and autonomic symptoms yearly over 5 years of follow-up. Dopamine transporter imaging was also performed at baseline and the 1-, 2-, and 4-year follow-up visits. ResultsThe late-onset group had a mean decrease of 0.35 more points per year in the Montreal Cognitive Assessment (MoCA) scores (p = 0.008) and increases of 0.32 more points in the 15-item Geriatric Depression Scale scores (p = 0.002) and 0.72 more points in the State-Trait Anxiety Inventory-state scores (p = 0.022) compared to the middle-onset group. The young-onset group had a mean decrease of 0.22 fewer points per year in the MoCA scores (p = 0.002) than the middle-onset group. The other non-motor progression did not differ among the groups. No significant differences were found between the late-onset, middle-onset, and young-onset groups in the changes of striatal DAT binding ratios. ConclusionCompared to middle-onset PD, late-onset PD showed a faster progression of cognitive impairment along with depression and anxiety, and young-onset PD showed a slower progression of cognitive impairment in the early phases of the disease. These differences do not appear to be associated with the longitudinal changes in striatal dopaminergic activities.

Detailed visual assessment of striatal dopaminergic depletion in patients with idiopathic normal pressure hydrocephalus: unremarkable or not?

BackgroundDopamine transporter (DAT) imaging may enable clinicians to discriminate idiopathic normal pressure hydrocephalus (iNPH) from other parkinsonian disorders. However, a specific pattern of dopaminergic loss in DAT imaging of iNPH patients remains to be further elucidated.MethodsIn this preliminary study, 11 patients with iNPH in our hospital between March 2017 and February 2019 were finally enrolled. A diagnosis of iNPH was made according to the two established criteria. For visual analysis of DAT imaging, a striatum was divided into five domains. A semi-quantitative visual assessment was performed with a consensus between a nuclear medicine specialist and an experienced neurologist who were blinded to the clinical diagnosis.ResultsStriatal dopaminergic deficits were abnormal in 90.9% (10/11) of patients with iNPH. The degree of dopaminergic reduction was mild and heterogeneous. However, a tendency of preferential striatal DAT loss in the caudate nucleus (90.9%, 10/11) than in the putamen (72.7%, 8/11) was observed, whereas ventral portion (9.1%, 1/11) was relatively preserved.ConclusionStriatal dopaminergic depletion might be mild and heterogeneous in patients with iNPH. These dopaminergic deficits were more common in the caudate nucleus than in the putamen, suggesting a pattern different from other degenerative parkinsonian disorders.

Is There Any Clinical Value of Adding 123I-Metaiodobenzylguanidine Myocardial Scintigraphy to 123I-Ioflupane (DaTscan) in the Differential Diagnosis of Parkinsonism?

The aim of the study is to evaluate the impact of myocardial I-metaiodobenzylguanidine (MIBG) in the diagnosis, clinical management, and differential diagnosis of Parkinson disease (PD) and non-PD parkinsonism. The study enrolled 41 patients with parkinsonism. An initial diagnosis was reached after thorough clinical and imaging evaluation. After 2 to 5 years of follow-up, a final diagnosis was established. All patients underwent, soon after their initial visit, presynaptic striatal DaT scintigraphy with I-FP-CIT (DaTscan) and I-MIBG myocardial scintigraphy. DaTscan is not specific to distinguish among different types of neurodegenerative parkinsonism. I-MIBG myocardial scintigraphy displays the functional status of cardiac sympathetic nerves, which is reduced in PD/dementia with Lewy bodies (DLB) and normal in atypical parkinsonian syndromes and secondary or nondegenerative parkinsonism. No patients showed adverse effects during or after both scintigraphies. A positive DaTscan was found in all patients in the PD/DLB group (17/17) and in 15 of 24 patients in the non-PD group. Myocardial I-MIBG scintigraphy was associated with lower sensitivity (82% vs 100%) but higher specificity than DaTscan (79% vs 38%) in diagnosis PD/DLB from non-PD parkinsonism. A positive scan result on both techniques, to confirm diagnosis of PD/DLB, significantly improved the specificity of DaTscan, from 38% to 75%, with no reduction in sensitivity. Myocardial I-MIBG imaging provides complementary value to I-FP-CIT in the proper diagnosis, treatment plan, and differential diagnosis between PD and other forms of parkinsonism.

Chronic abdominal vagus stimulation increased brain metabolic connectivity, reduced striatal dopamine transporter and increased mid-brain serotonin transporter in obese miniature pigs

Background/objectiveChanges in brain metabolism has been investigated thoroughly during unilateral cervical chronic vagal stimulation in epileptic or depressive patients. Bilateral stimulation of the abdominal vagus (aVNS) has received less attention despite the reduction in body weight and an altered feeding behavior in obese animals that could be clinically relevant in obese individuals. Our study aims to examine the changes in brain glucose metabolism (CMRglu) induced by aVNS in obese adult miniature pigs. Dopamine (DAT) and serotonin transporters (SERT) were also quantified to further understand the molecular origins of the alterations in brain metabolism.Subjects/methodsPairs of stimulating electrodes were implanted during laparoscopy on both abdominal vagal trunks in 20 obese adult’s miniature pigs. Half of the animals were permanently stimulated while the remaining were sham stimulated. Two months after the onset of stimulation, dynamic 18FDG PET and 123I-ioflupane SPECT were performed. Food intake, resting energy expenditure and fat deposition were also assessed longitudinally.ResultsFood intake was halved and resting energy expenditure was increased by 60% in aVNS group compared to sham. The gain in body weight was also 38% less in aVNS group compared to sham. Brain metabolic connectivity increased between numerous structures including striatum, mid-brain, amygdala and hippocampus. On the contrary, increased CMRglu were restricted to the thalamus, the periaqueducal grey and the amygdala. DAT binding potential was decreased by about one third in the striatum while SERT was about doubled in the midbrain.ConclusionsOur findings demonstrated that aVNS reduced weight gain as a consequence of diminished daily food intake and increased resting energy expenditure. These changes were associated with enhanced connectivity between several brain areas. A lower striatal DAT together with a doubled mid-brain SERT were likely causative for these changes.

Striatal DAT and extrastriatal SERT binding in early-stage Parkinson's disease and dementia with Lewy bodies, compared with healthy controls: An 123I-FP-CIT SPECT study.

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are thought to be part of a spectrum: both have a clinical profile including symptoms associated with dopaminergic and serotonergic loss, yet few imaging studies have focused on serotonergic neurodegeneration in both disorders. We aimed to study degeneration of terminals with dopamine and serotonin transporter (DAT and SERT, respectively) in patients with early-stage PD and DLB relative to healthy controls, using 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (123I-FP-CIT) single photon emission computed tomography (SPECT).We conducted region of interest (ROI) and voxel-based analyses on 123I-FP-CIT SPECT scans. Using the cerebellum as a reference region, we determined binding ratios (BRs) for bilateral ROIs in the DAT-rich striatum (head of the caudate nucleus and posterior putamen) and SERT-rich extrastriatal brain regions (thalamus, hypothalamus and hippocampus). We compared BRs in PD and DLB patients with BRs in healthy controls (all groups: n = 16).Both PD and DLB patients had lower striatal 123I-FP-CIT BRs than healthy controls for the bilateral caudate head (PD—left: F(1,29) = 28.778, P < .001, ω2 = 0.35; right: F(1,29) = 35.338, P < .001, ω2 = 0.42; DLB—left: F(1,29) = 28.241, P < .001, ω2 = 0.31; right: F(1,29) = 18.811, P < .001, ω2 = 0.26) and bilateral posterior putamen (PD—left: F(1,29) = 107.531, P < .001, ω2 = 0.77; right: F(1,29) = 87.525, P < .001, ω2 = 0.72; DLB—left: F(1,29) = 39.910, P < .001, ω2 = 0.48; right: F(1,29) = 26.882, P < .001, ω2 = 0.38). DLB patients had lower hypothalamic 123I-FP-CIT BRs than healthy controls (F(1,29) = 6.059, P = .020, ω2 = 0.12). In the voxel-based analysis, PD and DLB patients had significantly lower striatal binding than healthy controls.Both PD patients in the early disease stages and DLB patients have reduced availability of striatal DAT, and DLB patients lower hypothalamic SERT compared with healthy controls. These observations add to the growing body of evidence that PD and DLB are not merely dopaminergic diseases, thereby providing additional clinicopathological insights.

Dopamine transporter imaging with [18F]FE-PE2I PET and [123I]FP-CIT SPECT\u2014a clinical comparison

BackgroundDopamine transporter (DAT) imaging may be of diagnostic value in patients with clinically suspected parkinsonian disease. The purpose of this study was to compare the diagnostic performance of DAT imaging with positron emission computed tomography (PET), using the recently developed, highly DAT-selective radiopharmaceutical [18F]FE-PE2I (FE-PE2I), to the commercially available and frequently used method with [123I]FP-CIT (FP-CIT) single-photon emission computed tomography (SPECT) in early-stage idiopathic parkinsonian syndrome (PS).MethodsTwenty-two patients with a clinical de novo diagnosis of PS and 28 healthy controls (HC) participating in an on-going clinical trial of FE-PE2I were analyzed in this study. Within the trial protocol, participants are clinically reassessed 2 years after inclusion. A commercially available software was used for automatic calculation of FP-CIT-specific uptake ratio (SUR). MRI-based volumes of interest combined with threshold PET segmentation were used for FE-PE2I binding potential relative to non-displaceable binding (BPND) quantification and specific uptake value ratios (SUVR).ResultsPET with FE-PE2I revealed significant differences between patients with a clinical de novo diagnosis of PS and healthy controls in striatal DAT availability (p < 0.001), with excellent accuracy of predicting dopaminergic deficit in early-stage PS. The effect sizes were calculated for FE-PE2I BPND (Glass’s Δ = 2.95), FE-PE2I SUVR (Glass’s Δ = 2.57), and FP-CIT SUR (Glass’s Δ = 2.29). The intraclass correlation (ICC) between FE-PE2I BPND FP-CIT SUR was high in the caudate (ICC = 0.923), putamen (ICC = 0.922), and striatum (ICC = 0.946), p < 0.001. Five of the 22 patients displayed preserved striatal DAT availability in the striatum with both methods. At follow-up, a non-PS clinical diagnosis was confirmed in three of these, while one was clinically diagnosed with corticobasal syndrome. In these patients, FE-PE2I binding was also normal in the substantia nigra (SN), while significantly reduced in the remaining patients. FE-PE2I measurement of the mean DAT availability in the putamen was strongly correlated with BPND in the SN (R = 0.816, p < 0.001). Olfaction and mean putamen DAT availability was correlated using both FE-PE2I BPND and FP-CIT SUR (R ≥ 0.616, p < 0.001).ConclusionDAT imaging with FE-PE2I PET yields excellent basic diagnostic differentiation in early-stage PS, at least as good as FP-CIT SPECT.

Dopaminergic degeneration induces early posterior cortical thinning in Parkinson's disease

BackgroundCognitive decline in Parkinson's disease (PD) is a highly prevalent condition with no effective treatment. Cortical atrophy is thought to promote its development but to design optimal therapeutic approaches in this clinical setting we need to understand the physiopathological mechanisms leading to this disorder. ObjectiveTo characterize the impact of dopaminergic degeneration on cortical integrity in early PD. MethodsWe studied 87 recently-diagnosed PD patients and 38 healthy controls from the Parkinson's Progression Marker Initiative who underwent I123-ioflupane SPECT (DATSCAN) and T1-MRI imaging. Using Freesurfer 6.0, we characterized baseline and longitudinal (one-year) correlations between striatal DAT uptake and cortical thickness. We also addressed the association between these imaging biomarkers and cognitive measures. ResultsReduced DAT uptake in PD patients was associated with cross-sectional and longitudinal cortical thinning in frontal and posterior-cortical brain regions. Imaging parameters correlated with cognitive indicators in multiple domains that extend beyond frontal-executive tasks. Dopaminergic medication attenuated the longitudinal loss of cortical integrity in frontal and a subset of parietal regions, but not in other key regions such as the precuneus. DiscussionTo date, posterior cortical alterations in PD, known to play a major role in the development of PD-dementia, have mainly been attributed to a cholinergic degeneration occurring in later stages of the disease. Our results suggest that dopamine loss also promotes posterior-cortical atrophy from the very early stages of Parkinson's disease, which may have potential clinical and therapeutic implications.