Head‐to‐head comparison of 18F‐FP‐CIT and 123I‐FP‐CIT for dopamine transporter imaging in patients with Parkinson's disease: A preliminary study

¹²³I‐FP‐CIT and ¹⁸F‐FP‐CIT are radiotracers which are widely used to diagnose Parkinson's disease (PD). However, to our knowledge, no studies to date have made head‐to‐head comparisons between ¹²³I‐FP‐CIT and ¹⁸F‐FP‐CIT. Therefore, in this study, ¹²³I‐FP‐CIT SPECT/CT was compared with ¹⁸F‐FP‐CIT PET/CT in the same cohort of subjects. Patients with PD and essential tremor (ET) underwent ¹²³I‐FP‐CIT SPECT/CT and ¹⁸F‐FP‐CIT PET/CT. Visual and semiquantitative analyses were conducted. The specific binding ratio (SBR) and putamen to caudate ratio (PCR) were compared between subjects who underwent ¹²³I‐FP‐CIT SPECT/CT and ¹⁸F‐FP‐CIT PET/CT. Visual analysis showed that the striatal uptake of both radiotracers was decreased in the PD group, whereas striatal uptake was intact in the ET group. The SBR between ¹²³I‐FP‐CIT SPECT/CT and ¹⁸F‐FP‐CIT PET/CT showed a positive correlation (r = .78, p < .01). However, the mean SBRs on ¹⁸F‐FP‐CIT PET/CT were higher than those on ¹²³I‐FP‐CIT SPECT/CT (2.19 ± .87 and 1.22 ± .49, respectively; p < .01). The PCRs in these two modalities were correlated with each other (r = .71, p < .01). The mean PCRs on ¹⁸F‐FP‐CIT PET/CT were not significantly higher than those on ¹²³I‐FP‐CIT SPECT/CT (1.31 ± .19 and 0.98 ± .06, respectively; p = .06). These preliminary results indicate that the uptake of both ¹²³I‐FP‐CIT and ¹⁸F‐FP‐CIT was decreased in the PD group when compared with the ET controls. Visual analyses using both methods did not affect the diagnostic accuracy in this study. However, semiquantitative analysis indicated a better contrast of ¹⁸F‐FP‐CIT PET/CT relative to ¹²³I‐FP‐CIT SPECT/CT.     

Differences in nigro‐striatal impairment in clinical variants of early Parkinson’s disease: evidence from a FP‐CIT SPECT study

Introduction: In idiopathic Parkinson’s disease (PD), two different clinical phenotypes are usually distinguished: a tremor dominant variant (TD) and an akinetic‐rigid type (ART). TD patients are characterized by a slower disease progression and a minor cognitive impairment. Striatal density of DAT, as quantified by FP‐CIT SPECT, has been reported to correlate with rigidity and akinesia but not with tremor. Objective: To evaluate FP‐CIT uptake in TD and ART phenotypes. Methods: We retrospectively evaluated from our database the pre‐synaptic nigro‐striatal function of 24 patients with TD‐PD and 38 patients with ART‐PD who underwent a FP‐CIT SPECT within 1 year from disease onset. Results: Disease duration, age at the time of SPECT scan and disease severity as measured with Unified Parkinson’s Disease Rating scale part III (UPDRS III) were not statistically different between the two groups. Putamen contralateral to the most clinically affected side showed a lower FP‐CIT uptake in ART patients compared to TD patients. No statistically significant differences emerged when considering bilateral caudate and ipsilateral putaminal uptake, as well as asymmetry indices and caudate/putamen ratios. FP‐CIT contralateral putaminal uptake correlated with the severity of rigidity and hypokinesia but not with tremor. Conclusions: These data suggest that other neurotransmitter systems apart from the nigro‐striatal dopaminergic system are involved in the generation of Parkinsonian tremor, and they are consistent with previous evidence of a lack of correlation between tremor severity and FP‐CIT uptake. Putaminal relative sparing in TD patients could partially explain the slower disease progression reported in this PD phenotype.     

[123I] FP‐CIT spect study in vascular parkinsonism and Parkinson's disease

There is substantial evidence to support a role for small vessel disease (SVD) as a cause for vascular parkinsonism (VP). Using [¹²³I] FP‐CIT SPECT (single photon emission computed tomography), we have tried to determine whether VP patients have pre‐synaptic dopaminergic function similar to PD patients, and whether the severity of parkinsonian symptoms as well as the levodopa response in VP patients are correlated with pre‐synaptic dopaminergic dysfunction. Thirteen patients fulfilling operational clinical criteria for VP had [¹²³I] FP‐CIT scans. Mean [¹²³I] FP‐CIT uptake in the basal ganglia was significantly lower in VP patients than in healthy controls, and the asymmetry index was not significantly different between these groups. In contrast, compared with the PD group, only the mean asymmetry index was significantly lower in VP patients. None of the parameters measured was significantly different between VP patients who had an insidious onset of parkinsonism (VPi) and those who had an acute onset (VPa). There was a significant correlation between the bilateral basal ganglia FP‐CIT uptake reduction in the VP patients and UPDRS motor scores, but not with the mean % reduction in motor UPDRS after levodopa. We suggest that in the majority of VP patients, pre‐synaptic dopaminergic function is reduced. The presence of a rather symmetrical FP‐CIT uptake in the basal ganglia may help to distinguish VP from PD and could therefore be used as a criterion for the clinical diagnosis of VP. © 2007 Movement Disorder Society     

Striatal dopamine transporter imaging correlates with depressive symptoms and tower of London task performance in Parkinson's disease

We studied whether the ¹²³I‐FP‐CIT uptake in the striatum correlates with depressive symptoms and cognitive performance in patients with Parkinson's disease (PD). Twenty patients with PD without major depression and/or dementia (mean age 61.7 ± 12.7 years) underwent the ¹²³I‐FP‐CIT SPECT. Depressive symptoms and cognitive performance were assessed in the ON state. The ratios of striatal to occipital binding for the entire striatum, putamina, and putamen to the caudate (put/caud) index were calculated in the basal ganglia. The association between neuropsychiatric measures and dopamine transporter (DAT) availability was calculated; multiple regression analysis was used to assess association with age and disease duration. We found significant correlations between Montgomery and Asberg Depression Rating Scale (MARDS) and Tower of London (TOL) task scores and ¹²³I‐FP‐CIT uptake in various striatal ROIs. Multiple regression analysis confirmed the significant relationship between TOL performance and put/caud ratio (P = 0.001) and to age (P = 0.001), and between MADRS and left striatal (P = 0.005) and putaminal DAT availability (P = 0.003). Our pilot study results demonstrate that imaging with ¹²³I‐FP‐CIT SPECT appears to be sensitive for detecting dopaminergic deficit associated with mild depressive symptoms and specific cognitive dysfunction in patients with PD, yet without a current depressive episode and/or dementia. © 2008 Movement Disorder Society     

Dopaminergic modulation of resting‐state functional connectivity in de novo patients with Parkinson's disease

Parkinson's disease (PD) is characterized by degenerative changes of nigral dopamine neurons, resulting in the dopaminergic denervation of the striatum. Resting state networks studies have demonstrated that dopamine modulates distinct network connectivity patterns in both a linear and a nonlinear fashion, but quantitative analyses of dopamine‐dependent functional connectivity secondary to PD pathology were less informative. In the present study, we performed a correlation analysis between striatal dopamine levels assessed quantitatively by FP‐CIT positron emission tomography imaging and resting‐state functional connectivity in 23 drug naïve de novo patients with PD to elucidate dopamine‐dependent functional networks. The major finding is that the patterns of dopamine‐dependent positive functional connectivity varied depending on the location of striatal seeds. Dopamine‐dependent functional connectivity with the caudate predominantly overlay pericentral cortical areas, whereas dopamine‐dependent structures functionally connected with the posterior putamen predominantly involved cerebellar areas. The dorsolateral frontal area overlapped as a dopamine‐dependent cortical region that was positively connected with the anterior and posterior putamen. On the other hand, cortical areas where functional connectivity from the posterior cingulate was negatively correlated with dopaminergic status in the posterior putamen were localized in the left anterior prefrontal area and the parietal area. Additionally, functional connectivity between the anterior putamen and mesiofrontal areas was negatively coupled with striatal dopamine levels. The present study demonstrated that dopamine‐dependent functional network connectivity secondary to PD pathology mainly exhibits a consistent pattern, albeit with some variation. These patterns may reflect the diverse effects of dopaminergic medication on parkinsonian‐related motor and cognitive performance. Hum Brain Mapp 35:5431–5441, 2014. © 2014 Wiley Periodicals, Inc .     

Residual striatal dopaminergic nerve terminals in very long‐standing Parkinson's disease: A single photon emission computed tomography imaging study

Molecular imaging studies of Parkinson's disease (PD) progression mostly focus on the first 5 years after disease onset, demonstrating rapid initial nigrostriatal neuronal loss. The fate of residual functional dopaminergic nerve terminals in patients with long‐standing PD has not yet been specifically explored. Therefore, we performed [¹²³I]‐FP‐CIT single photon emission computed tomography (SPECT) in 15 patients with very long‐standing PD (mean disease duration 20.6 ± 6.3 years). Measurable uptake of [¹²³I]‐FP‐CIT was still detected in the striata of all patients. As seen in early stages, reduction of tracer uptake in the putamen was more prominent than in the caudate nucleus. Asymmetry in tracer uptake between the two putamen and caudate nuclei was preserved. These findings indicate that degeneration of dopaminergic neurons in PD is not total even after many years of illness. Data should be considered in exploring underlying causes of progressive loss of nigrostriatal dopaminergic neurons and development of future novel dopaminergic therapeutic strategies in PD. © 2010 Movement Disorder Society     

Severity of neuropsychiatric symptoms and dopamine transporter levels in dementia with Lewy bodies: A 123I‐FP‐CIT SPECT study

Neuropsychiatric symptoms are frequent in dementia with Lewy bodies (DLB). Dopamine transporter (DAT) imaging with ¹²³I‐labeled ligand N‐δ‐(fluoropropyl)‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)tropene (¹²³I‐FP‐CIT), which reliably measures midbrain dopaminergic dysfunction, has provided important evidence on the neurobiological substrate of some of these symptoms including apathy and depression. However, little is known on DAT levels and other distressing symptoms such as delusions and hallucinations. Therefore, ¹²³I‐FP‐CIT imaging was performed in 18 well‐characterized patients with DLB, and striatal DAT levels were correlated with the frequency/severity ratings of several neuropsychiatric symptoms. A wide range of neuropsychiatric symptoms could be observed in the sample. Significant correlations were observed between decreased striatal DAT levels and visual hallucinations. Although there were no correlations between striatal DAT levels and other neuropsychiatric symptoms, when considering the putamen and the caudate nucleus separately, delusions, depression, and apathy were inversely correlated to decreased caudate DAT levels. Theseresults provide intriguing evidence on the involvement of the mesocortical dopaminergic pathways in neuropsychiatric symptoms in DLB. © 2009 Movement Disorder Society     

Midbrain serotonin transporters in de novo and L‐DOPA‐treated patients with early Parkinson’s disease – a [123I]‐ADAM SPECT study

Background: Dopaminergic availability is known to linearly decline in Parkinson’s disease (PD). In contrast, temporal characteristics of serotonergic markers like the serotonin transporter (SERT) in relation to clinical staging of PD and dopaminergic cell loss are less clear. This study investigated SERT availability using [¹²³I]‐ADAM and single‐photon emission tomography (SPECT) in drug‐naive, de novo patients, i.e., in a PD stage where dopaminergic decline starts to lead to the occurence of the characteristic motor symptoms. Methods: Nine de novo patients with PD and 9 age‐matched healthy controls were studied. Measurements were repeated after 3 months of levodopa treatment in patients with PD, and dopaminergic transporter (DAT) binding was examined at baseline using [¹²³I]‐FP‐CIT SPECT. Results: No alterations of SERT availability were found between groups, and neither correlation between SERT and DAT nor effects of levodopa treatment on SERT was found in patients with PD. Conclusions: These preliminary findings indicate that midbrain SERT is preserved in unmedicated patients at this early stage of PD, supporting the view that serotonergic decline temporally follows dopaminergic cell loss.     

Dopaminergic deficit is not the rule in orthostatic tremor

Involvement of the dopaminergic system in orthostatic tremor is controversial. The aim of this study was to detect possible dopaminergic denervation in primary orthostatic tremor (OT). Twelve consecutive patients with a firm diagnosis of primary orthostatic tremor were compared with age‐matched normal controls. All the patients had a neurological examination, surface polymyography, and quantification of striatal dopamine transporters with ¹²³I‐FP‐CIT SPECT imaging. There was no significant difference in ¹²³I‐FP‐CIT SPECT findings between controls and patients with OT. Longstanding primary orthostatic tremor is not necessarily associated with ¹²³I‐FP‐CIT SPECT abnormalities, as 8 of our patients had more than a 10‐year history of OT. Primary orthostatic tremor without dopaminergic denervation remains a valid entity, although representing only a subtype of high‐frequency OT. A new role may emerge for ¹²³I‐FP‐CIT SPECT in distinguishing between patients whose symptoms will be restricted to OT throughout the disease course and patients at an increased risk of developing PD. © 2008 Movement Disorder Society     

Functional brain imaging in pure akinesia with gait freezing: [18F] FDG PET and [18F] FP‐CIT PET analyses

Pure akinesia with gait freezing (PAGF) has characteristic features, including freezing of gait and prominent speech disturbance without rigidity or tremor. The purpose of this study was to investigate changes in brain glucose metabolism and presynaptic dopaminergic function in PAGF. By using [¹⁸F] fluorodeoxyglucose (FDG) PET, 11 patients with PAGF were compared with 14 patients with probable progressive supranuclear palsy (PSP), 13 patients with Parkinson's disease (PD), and 11 normal controls. [¹⁸F] N‐(3‐fluoropropyl)‐2β‐carbon ethoxy‐3β‐(4‐iodophenyl) nortropane (FP‐CIT) PET was performed in 11 patients with PAGF and with 10 normal controls. The PAGF patients showed decreased glucose metabolism in the midbrain when compared with normal controls. PSP patients showed a similar topographic distribution of glucose hypometabolism with additional areas, including the frontal cortex, when compared with normal controls. The FP‐CIT PET findings in patients with PAGF revealed severely decreased uptake bilaterally in the basal ganglia. These findings suggest that both PAGF and PSP may be part of the same pathophysiologic spectrum of disease. However, the reason why PAGF manifests clinically in a different manner needs to be further elucidated. © 2008 Movement Disorder Society     

Fluorodopa is a Promising Fluorine‐19 MRI Probe for Evaluating Striatal Dopaminergic Function in a Rat Model of Parkinson's Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra projecting to the striatum. It has been estimated that approximately 80% of the striatal dopamine and 50% of nigral dopaminergic neurons are lost before the onset of typical motor symptoms, indicating that early diagnosis of PD using noninvasive imaging is feasible. Fluorine‐19 (¹⁹F) magnetic resonance imaging (MRI) represents a highly sensitive, easily available, low‐background, and cost‐effective approach to evaluate dopaminergic function using non‐radioactive fluorine‐containing dopaminergic agents. The aim of this study was to find a potent ¹⁹F MRI probe to evaluate dopaminergic presynaptic function in the striatum. To select candidates for ¹⁹F MRI probes, we investigated the following eight non‐radioactive fluorine‐containing dopaminergic agents: fluorodopa (F‐DOPA), F‐tyrosine, haloperidol, GBR13069 duhydrochloride, GBR12909 duhydrochloride, 3‐bis‐(4‐fluorophenyl) methoxytropane hydrochloride, flupenthixol, and fenfluramine. In ¹⁹F nuclear magnetic resonance measurements, F‐tyrosine and F‐DOPA displayed a relatively higher signal‐to‐noise ratio value in brain homogenates than in others. F‐DOPA, but not F‐tyrosine, induced the rotational behavior in a 6‐hydroxydopamine (6‐OHDA)‐induced hemiparkinsonian rat model. In addition, a significantly high amount of F‐DOPA accumulated in the ipsilateral striatum of hemiparkinsonian rats after the injection. We performed ¹⁹F MRI in PC12 cells and isolated rat brain using a 7T MR scanner. Our findings suggest that F‐DOPA is a promising ¹⁹F MRI probe for evaluating dopaminergic presynaptic function in the striatum of hemiparkinsonian rats. © 2016 Wiley Periodicals, Inc.     

Cognitive executive impairment and dopaminergic deficits in de novo Parkinson's disease

Cognitive impairment in Parkinson's disease (PD) is common and does directly impact patients' everyday functioning. However, the underlying mechanisms of early cognitive decline are not known. This study explored the association between striatal dopaminergic deficits and cognitive impairment within a large cohort of early, drug‐naïve PD patients and tested the hypothesis that executive dysfunction in PD is associated with striatal dopaminergic depletion. A cross‐sectional multicenter cohort of 339 PD patients and 158 healthy controls from the Parkinson's Progression Markers Initiative study was analyzed. Each individual underwent cerebral single‐photon emission CT (SPECT) and a standardized neuropsychological assessment with tests of memory as well as visuospatial and executive function. SPECT imaging was performed with [¹²³I]FP‐CIT, and specific binding ratios in left and right putamen and caudate nucleus were calculated. The association between specific binding ratios, cognitive domain scores, and age was analyzed using Pearson's correlations, partial correlation, and conditional process analysis. A small, but significant, positive association between total striatal dopamine transporter binding and the attention/executive domain was found (r = 0.141; P = 0.009) in PD, but this was not significant after adjusting for age. However, in a moderated mediation model, we found that cognitive executive differences between controls and patients with PD were mediated by an age‐moderated striatal dopaminergic deficit. Our findings support the hypothesis that nigrostriatal dopaminergic deficit is associated with executive impairment, but not to memory or visuospatial impairment, in early PD. © 2014 International Parkinson and Movement Disorder Society     

Structural covariance networks of striatum subdivision in patients with Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder associated with the striatum. Previous studies indicated that subdivisions of the striatum with distinct functional connectivity profiles contribute to different pathogeneses in PD. Segregated structural covariance (SC) pattern between the striatum and neocortex observed in healthy subjects, however, remain unknown in PD. The purpose of this study is to map and compare the subregional striatal SC network organization between 30 healthy controls and 48 PD patients and to investigate their association with the disease severity. The striatal SC network was statistically inferred by correlating the mean gray matter (GM) volume of six striatal subdivisions (including the bilateral dorsal caudate, superior ventral striatum, inferior ventral striatum, dorsal caudal putamen, dorsal rostral putamen, and ventral rostral putamen) with the entire neocortical GM volume in voxel‐wise manner. The PD patients revealed marked atrophy in the striatum, cerebellum, and extra‐striatum neocortices. As predicted, segregated striatal SC network patterns were observed in both groups. This suggests that in PD, pathological processes occurring in the striatum affect the same striato‐cortical networks that covary with the striatum in healthy brains. The PD patients further demonstrated atypical striatal SC patterns between the caudate, parahippocampus temporal cortices, and cerebellum, which corresponded to dopaminergic associated network. The areas with significant group differences in SC were further associated with disease severity. Our findings support previous studies indicating that PD is associated with altered striato‐cortical networks, and suggest that structural changes in the striatum may result in a cascade of alterations in multiple neocortices. Hum Brain Mapp 36:1567–1584, 2015. © 2014 Wiley Periodicals, Inc .     

Extensive exploration of a novel rat model of Parkinson's disease using partial 6‐hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons constituting the nigrostriatal pathway. Neuroinflammation, related to microglial activation, plays an important role in this process. Exploration of animal models of PD using neuroimaging modalities allows to better understand the pathophysiology of the disease. Here, we fully explored a moderate lesion model in the rat in which 6‐hydroxydopamine was unilaterally delivered in three sites along the striatum. The degenerative process was assessed through in vivo Positron Emission Tomography (PET) imaging and in vitro autoradiographic quantitation of the striatal dopamine transporter (DAT) and immunostaining of tyrosine hydroxylase (TH). The microglial activation was studied through in vitro autoradiographic quantitation of the 18 kDa translocator protein (TSPO) in the striatum and CD11b staining in the SN. In addition, a targeted metabolomics exploration was performed in both these structures using mass spectrometry coupled to HPLC. Our results showed a reproducible decrease in the striatal DAT density associated with a reduction in the number of TH‐positive cells in the SN and striatum, reflecting a robust moderate degeneration of nigrostriatal DA neurons. In addition, we observed strong microglia activation in both the striatum and SN ipsilateral to the lesion, highlighting that this moderate degeneration of DA neurons was associated with a marked neuroinflammation. Our metabolomics studies revealed alterations of specific metabolites and metabolic pathways such as carnitine, arginine/proline, and histidine metabolisms. These results bring new insights in the PD mechanism knowledge and new potential targets for future therapeutic strategies.     

6‐hydroxydopamine‐induced Parkinson's disease‐like degeneration generates acute microgliosis and astrogliosis in the nigrostriatal system but no bioluminescence imaging‐detectable alteration in adult neurogenesis

Parkinson's disease is a slowly progressing neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra (SN), leading to severe impairment in motor and non‐motor functions. Endogenous subventricular zone (SVZ) neural stem cells constantly give birth to new cells that might serve as a possible source for regeneration in the adult brain. However, neurodegeneration is accompanied by neuroinflammation and dopamine depletion, potentially compromising regeneration. We therefore employed in vivo imaging methods to study striatal deafferentation (N‐ω‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐[¹²³I]iodophenyl)nortropane single photon emission computed tomography, DaTscan^™) and neuroinflammation in the SN and striatum (N,N‐diethyl‐2‐(2‐(4‐(2‐[¹⁸F]fluoroethoxy)phenyl)‐5,7‐dimethylpyrazolo[1,5‐a]pyrimidin‐3‐yl)acetamide positron emission tomography, [¹⁸F]DPA‐714 PET) in the intranigral 6‐hydroxydopamine Parkinson's disease mouse model. Additionally, we transduced cells in the SVZ with a lentivirus encoding firefly luciferase and followed migration of progenitor cells in the SVZ–olfactory bulb axis via bioluminescence imaging under disease and control conditions. We found that activation of microglia in the SN is an acute process accompanying the degeneration of dopaminergic cell bodies in the SN. Dopaminergic deafferentation of the striatum does not influence the generation of doublecortin‐positive neuroblasts in the SVZ, but generates chronic astrogliosis in the nigrostriatal system.     

The implication of nigrostriatal dopaminergic degeneration in the pathogenesis of REM sleep behavior disorder

Background and purpose: The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is not clear despite its frequent association with Parkinson’s disease (PD). We investigated whether the nigrostriatal dopaminergic system is involved in the development of idiopathic RBD. Methods: Fourteen patients with RBD, 14 patients with PD and 12 normal controls were included in the study. The diagnosis of RBD was confirmed on polysomnography. All the participants performed single‐photon emission computed tomography imaging 3 h after injection of [¹²³I]FP‐CIT. During REM sleep of the RBD patients, each 30‐s epoch was rated as ‘tonic’ when there was at least 50% of tonically maintained chin electromyography (EMG) activity in the epoch. Phasic EMG activities were calculated as the percentage of 3‐s mini‐epoch containing phasic EMG events (leg and chin, separately). Results: The RBD patients showed a trend of lower binding in the striatum than the normal controls (P = 0.07), and the significance was revealed in the putamen (P = 0.02). However, in 11 individual cases of the 14 RBD patients, the dopamine transporter (DAT) densities in the putamen still remained within the normal range. In the RBD patients, there was no correlation between EMG activities and DAT densities. Conclusions: Nigrostriatal dopaminergic degeneration could be a part of the pathogenesis of RBD, but not essential for the development of RBD. The lack of correlation between RBD severity and DAT densities suggests that another pathogenic process not related to nigrostriatal dopaminergic transmission may be implicated in RBD.     

Substantia nigra echogenicity: A structural correlate of functional impairment of the dopaminergic striatal projection in Parkinson's disease

Transcranial sonography (TCS) reveals abnormal spatial extension of substantia nigra (SN) echogenicity in a high proportion of patients with Parkinson's disease (PD). It has been proposed that this abnormality represents a structural trait that is mechanistically distinct from degeneration of dopaminergic nigrostriatal projection neurons. We sought to clarify the relationship between sonographic abnormalities of SN and dysfunction of striatal dopaminergic neurotransmission. We studied 50 patients with PD. The spatial extension of the echogenic SN area was compared with the activity of presynaptic striatal dopamine reuptake transporters, assessed in the same patients by I‐123‐2‐beta‐carbomethoxy‐3‐beta‐(4‐iodophenyl)‐tropane (β‐CIT) single‐photon emission computed tomography (SPECT). Extension of echogenic SN area correlated (inversely) with striatal activity of presynaptic dopamine reuptake transporter in PD patients (R = ?0.417; P = 0.003) and with the equivalent levodopa dose (R = 0.380; P = 0.006; linear regression analysis). Findings support the hypothesis that in PD abnormal extension of echogenic SN area provides a direct structural marker of degeneration of SN neurons. Therefore, in PD, TCS and β‐CIT assess pathophysiologically related phenomena. © 2009 Movement Disorder Society     

Resting‐state frontostriatal functional connectivity in Parkinson's disease–related apathy

One of the most common neuropsychiatric symptoms in Parkinson's disease (PD) is apathy, affecting between 23% and 70% of patients and thought to be related to frontostriatal dopamine deficits. In the current study, we assessed functional resting‐state frontostriatal connectivity and structural changes associated with the presence of apathy in a large sample of PD subjects and healthy controls, while controlling for the presence of comorbid depression and cognitive decline. Thirty‐one healthy controls (HC) and 62 age‐, sex‐, and education‐matched PD patients underwent resting‐state functional magnetic resonance imaging (MRI). Apathy symptoms were evaluated with the Apathy Scale (AS). The 11 Beck Depression Inventory‐II items that measure dysphoric mood symptoms as well as relevant neuropsychological scores were used as nuisance factors in connectivity analyses. Voxel‐wise analyses of functional connectivity between frontal lobes (limbic, executive, rostral motor, and caudal motor regions), striata (limbic, executive, sensorimotor regions), and thalami were performed. Subcortical volumetry/shape analysis and fronto‐subcortical voxel‐based morphometry were performed to assess associated structural changes. Twenty‐five PD patients were classified as apathetic (AS > 13). Apathetic PD patients showed functional connectivity reductions compared with HC and with non‐apathetic patients, mainly in left‐sided circuits, and predominantly involving limbic striatal and frontal territories. Similarly, severity of apathy negatively correlated with connectivity in these circuits. No significant effects were found in structural analyses. Our results indicate that the presence of apathy in PD is associated with functional connectivity reductions in frontostriatal circuits, predominating in the left hemisphere and mainly involving its limbic components. © 2015 International Parkinson and Movement Disorder Society     

Motor‐related circuit dysfunction in MSA‐P: Usefulness of combined whole‐brain imaging analysis

The aim of this study was to evaluate in vivo changes in the brain's macro‐ and microstructure (notably in the motor system) in the parkinsonian variant of multiple system atrophy (MSA‐P) and in Parkinson's disease (PD) and to characterize the cerebral anatomical differences between the two conditions. We used a combination of voxel‐based morphometry (VBM) and whole‐brain, voxel‐based diffusion tensor imaging analysis (VB‐DTI). Forty‐seven right‐handed subjects (14 MSA‐P patients, 19 PD patients, and 14 controls) were evaluated using VBM and VB‐DTI in an analysis of covariance (ANCOVA) with a significance threshold set to P < 0.005. In MSA‐P patients, VBM analysis revealed a lower density of grey matter (GM) in a motor‐related circuit (especially in the left primary motor cortex, PMC), relative to PD patients, and in the left supplementary motor area (SMA), relative to controls). Diffusion tensor imaging analysis revealed lower fractional anisotropy (FA) values in the left PMC and the right cerebellum in MSA‐P patients, compared with controls. Using a volumetric diffusion technique, our study revealed selective tissue degeneration in motor circuits, regardless of the volume loss detected in VBM and in agreement with pathology reports and clinical motor characteristics. Our findings suggest that MSA‐P is characterized by both macro‐ and microstructural changes in the sensorimotor circuit. © 2009 Movement Disorder Society     

Altered resting‐state connectivity in Huntington's Disease

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. Using resting‐state fMRI (rs‐fMRI) we investigated the functional integrity of resting‐state networks (RSN) in HD. 17 HD and 19 matched control participants were examined at a 3 Tesla MR scanner. After controlling for structural degeneration by means of voxel‐based morphometry, task‐free rs‐fMRI data were analyzed using Independent Component Analysis (ICA) and a dual‐regression approach in the context of genetic and clinical parameters. Further, we evaluated HD‐related differences in interregional connectivity between networks. RSN analysis showed a significant increase in intrinsic functional connectivity in the HD sample compared with controls, including the thalamus, striatum, prefrontal, premotor, and parietal maps. A subset of the Default Mode Network (DMN) was also affected. In the HD cohort, motor impairment correlated with higher network connectivity in mainly motor and parietal cortices. Deteriorating total functional capacity was additionally associated with higher connectivity in the striatum, thalamus, insular and frontal areas. This pattern of increased activity in intrinsic functional networks might suggest a reduced ability of intra‐network differentiation with clinical disease progression in HD. Finally, results showed reduced long‐range connectivity between parietal ICA components in HD compared to controls, indicating impaired functional coupling between interregional networks in HD. Our data demonstrates that functional connectivity is profoundly altered in HD, both within and between RSN. Rs‐fMRI analysis may provide additional valuable insights into neuronal dysfunctions beyond HD‐related structural degeneration and disruptions of functional circuits in HD. Hum Brain Mapp 35:2582–2593, 2014. © 2013 Wiley Periodicals, Inc .