Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease.

Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.

Diagnostic performance of molecular imaging methods in predicting the progression from mild cognitive impairment to dementia: an updated systematic review.

PURPOSE: Epidemiological and logistical reasons are slowing the clinical validation of the molecular imaging biomarkers in the initial stages of neurocognitive disorders. We provide an updated systematic review of the recent advances (2017-2022), highlighting methodological shortcomings. METHODS: Studies reporting the diagnostic accuracy values of the molecular imaging techniques (i.e., amyloid-, tau-, [18F]FDG-PETs, DaT-SPECT, and cardiac [123I]-MIBG scintigraphy) in predicting progression from mild cognitive impairment (MCI) to dementia were selected according to the Preferred Reporting Items for a Systematic Review and Meta-Analysis (PRISMA) method and evaluated with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Main eligibility criteria were as follows: (1) ≥ 50 subjects with MCI, (2) follow-up ≥ 3 years, (3) gold standard: progression to dementia or diagnosis on pathology, and (4) measures of prospective accuracy. RESULTS: Sensitivity (SE) and specificity (SP) in predicting progression to dementia, mainly to Alzheimer's dementia were 43-100% and 63-94% for [18F]FDG-PET and 64-94% and 48-93% for amyloid-PET. Longitudinal studies were lacking for less common disorders (Dementia with Lewy bodies-DLB and Frontotemporal lobe degeneration-FTLD) and for tau-PET, DaT-SPECT, and [123I]-MIBG scintigraphy. Therefore, the accuracy values from cross-sectional studies in a smaller sample of subjects (n > 20, also including mild dementia stage) were chosen as surrogate outcomes. DaT-SPECT showed 47-100% SE and 71-100% SP in differentiating Lewy body disease (LBD) from non-LBD conditions; tau-PET: 88% SE and 100% SP in differentiating DLB from Posterior Cortical Atrophy. [123I]-MIBG scintigraphy differentiated LBD from non-LBD conditions with 47-100% SE and 71-100% SP. CONCLUSION: Molecular imaging has a moderate-to-good accuracy in predicting the progression of MCI to Alzheimer's dementia. Longitudinal studies are sparse in non-AD conditions, requiring additional efforts in these settings.

Increased CSF DOPA Decarboxylase Correlates with Lower DaT-SPECT Binding: Analyses in Biopark and PPMI Cohorts.

BACKGROUND: Recent studies identified increased cerebrospinal fluid (CSF) DOPA decarboxylase (DDC) as a promising biomarker for parkinsonian disorders, suggesting a compensation to dying dopaminergic neurons. A correlation with 123I-FP-CIT-SPECT (DaT-SPECT) imaging could shed light on this link. OBJECTIVE: The objective is to assess the relationship between CSF DDC levels and DaT-SPECT binding values. METHODS: A total of 51 and 72 Parkinson's disease (PD) subjects with available DaT-SPECT and CSF DDC levels were selected from the PPMI and Biopark cohorts, respectively. DDC levels were analyzed using proximity extension assay and correlated with DaT-SPECT striatal binding ratios (SBR). All analyses were corrected for age and sex. RESULTS: CSF DDC levels in PD patients correlated negatively with DaT-SPECT SBR in both putamen and caudate nucleus. Additionally, SBR decreased with increased DDC levels over time in PD patients. CONCLUSION: CSF DDC levels negatively correlate with DaT-SPECT SBR in levodopa-treated PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Automatic quantification of REM sleep without atonia reliably identifies patients with REM sleep behavior disorder: a possible screening tool?

BACKGROUND: REM Sleep Behavior Disorder (RBD) is characterized by absence of physiological muscle atonia during REM sleep (REM sleep without atonia, RWA). Nigro-striatal dopaminergic impairment is a feature of Parkinson disease (PD) and can be identified in prodromal stages as well, such as idiopathic RBD (iRBD). Aims of this study are to explore the efficacy of an automatic RWA quantification in identifying RBD patients and the correlation between RWA and nigro-striatal dopaminergic function. METHODS: Forty-five iRBD, 46 PD with RBD, 24 PD without RBD patients and 11 healthy controls were enrolled in the Genoa Center (group A) and 25 patients with iRBD (group B) were enrolled in the Danish Center. Group A underwent brain [123I]FP-CIT-SPECT and group B underwent brain [18F]PE2I-PET as measures of nigro-striatal dopaminergic function. Chin muscle activity was recorded in all subjects and analyzed by applying a published automatic algorithm. Correlations between RWA and nigro-striatal dopaminergic function were explored. RESULTS: The automatic quantification of RWA significantly differentiated RBD from non-RBD subjects (AUC = 0.86), although with lower accuracy compared with conventional visual scoring (AUC = 0.99). No significant correlation was found between RWA and nigro-striatal dopaminergic function. CONCLUSION: The automatic quantification of RWA is a reliable tool to identify subjects with RBD and may be used as a first-line screening tool, but without correlations with nigro-striatal dopaminergic functioning.

The Impact of Drug Interactions on the Results of DAT-SPECT Imaging in a Specialty Movement Disorders Practice: A Retrospective Analysis of Outcomes.

INTRODUCTION: DAT-SPECT imaging is approved as a diagnostic tool for the evaluation of suspected Parkinsonian syndromes, but the FDA-approved package insert lists 16 potential drugs that may interfere with the image obtained. The clinical impact of these drugs on imaging results has not been established. This study aimed to determine the accuracy of DAT-SPECT imaging in assessing presynaptic dopaminergic denervation in the setting of these drugs. METHODS: This is a retrospective chart review of patients at a single center who underwent DAT-SPECT imaging while taking "contraindicated" drugs between December 2012 and December 2022. RESULTS: A total of 1,224 charts were screened, and 153 (12.5%) charts met the inclusion criteria. Bupropion (32%, n = 49) and sertraline (26%, n = 40) were the most common contraindicated drugs. The false-positive rate was 9.2%. CONCLUSION: This retrospective analysis supports the concern that certain drugs may interfere with DAT-SPECT imaging results, leading to potential false positives. This has implications for how clinicians interpret DAT-SPECT imaging in patients taking these medications and whether they should advise patients to stop these medications before a scan is performed.

Different z-score cut-offs for striatal binding ratio (SBR) of DaT SPECT are needed to support the diagnosis of Parkinson's Disease (PD) and dementia with Lewy bodies (DLB).

PURPOSE: A cut-off of -2 z-score for striatal or putaminal SBR has been to date arbitrarily used to define an abnormal DaT SPECT in patients with suspected neurodegenerative parkinsonism. We aimed to experimentally identify the most accurate z-score cut-offs for SBR of striatal and substriatal regions to independently discriminate PD and DLB, with respect to essential tremor (ET) and Alzheimer's disease (AD) respectively. METHODS: Two-hundred twenty-five patients undergoing DaT SPECT were enrolled (seventy-five de novo PD, eighty ET, fifty DLB, and twenty AD). Semiquantification was computed by means of Datquant® software which returns measures of striatal SBR and z-scores with respect to 118 healthy volunteers belonging to the Parkinson's Progression Markers Initiative (PPMI). ROC analysis was used to identify most accurate cut-offs for z-score for striatum and substriatal regions (clinical diagnosis at follow-up as gold standard). RESULTS: Posterior putamen of the most affected hemisphere (MAH) with a z-score cut-off of - 1.27 demonstrated the highest accuracy to differentiate between PD and ET (sensitivity 0.97, specificity 0.94). The whole putamen (z-score cut-off - 0.96) was the most accurate parameter to support the diagnosis of DLB (sensitivity 0.74, specificity 0.95). Putamen to caudate ratio was accurate to detect PD (especially in early stages) while not DLB patients. CONCLUSION: We experimentally demonstrated that different substriatal regions and cut-offs for z-score of SBR should be considered to support the diagnosis of either PD or DLB. The identified less conservative cut-offs showed higher sensitivity without a measurable reduction in specificity with respect to the arbitrary - 2 z-score.

Clinical characteristics and potential association to Parkinson's disease and dementia with Lewy bodies in patients with major depressive disorder who received maintenance electroconvulsive therapy: a retrospective chart review study.

BACKGROUND: Maintaining remission after electroconvulsive therapy (ECT) is clinically relevant in patients with depression, and maintenance ECT has been introduced in patients who fail to maintain remission after ECT. However, the clinical characteristics and biological background of patients who receive maintenance ECT are poorly understood. Thus, this study aimed to examine the clinical background of patients who underwent maintenance ECT. METHODS: Patients with major depressive disorder who underwent ECT followed by maintenance ECT (mECT group) and those who did not (acute ECT [aECT] group) were included. Clinical characteristics, including the results of neuroimaging examinations for Parkinson's disease (PD) and dementia with Levy body (DLB) such as myocardial 123I-metaiodobenzylguanidine (MIBG) scintigraphy and dopamine transporter imaging single-photon emission computerized tomography (DaT-SPECT), were compared between the groups. RESULTS: In total, 13 and 146 patients were included in the mECT and aECT groups, respectively. Compared to the aECT group, the mECT group showed a significantly higher prevalence of melancholic features (92.3% vs. 27.4%, p < 0.001) and catatonic features (46.2% vs. 9.6%, p = 0.002). Overall, 8 of the 13 patients in the mECT group and 22 of the 146 patients in the aECT group underwent neuroimaging examinations for PD/DLB. The rate of patients examined is significantly higher in the mECT group than in the aECT group (61.5% vs. 11.2%, p < 0.001). Among the groups examined, 7/8 patients in the mECT group and 16/22 patients in the aECT group showed relevant neuroimaging findings for PD/DLB; the positive rate was not significantly different between the two groups (87.5% vs. 72.7%, p = 0.638). CONCLUSIONS: Patients who receive acute and maintenance ECT may have underlying neurodegenerative diseases, including PD/DLB. Investigating the neurobiology of patients who receive maintenance ECT is important for developing appropriate treatments for depression.

Effect of cerebrospinal fluid area mask correction on 123I-FP-CIT SPECT images in idiopathic normal pressure hydrocephalus.

BACKGROUND: Cerebrospinal fluid (CSF) area mask correction reduces the influence of low [123I]-N-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane (123I-FP-CIT) accumulation in the volume of interest (VOI) by CSF area dilatation on the specific binding ratio (SBR) calculated using the Southampton method. We assessed the effect of CSF area mask correction on the SBR for idiopathic normal pressure hydrocephalus (iNPH) characterized by CSF area dilatation. METHODS: We enrolled 25 patients with iNPH who were assessed using 123I-FP-CIT single-photon emission computed tomography (SPECT) before shunt surgery or the tap test. The SBRs with and without CSF area mask correction were calculated, and changes in quantitative values were verified. Additionally, the number of voxels in the striatal and background (BG) VOI before and after CSF area mask correction were extracted. The number of voxels after correction was subtracted from that before correction, and the volume removed by the CSF area mask correction was calculated. The volumes removed from each VOI were compared to verify their effect on SBR. RESULTS: The images of 20 and 5 patients with SBRs that were decreased and increased, respectively, by CSF area mask correction showed that the volumes removed from the BG region VOI were higher and lower, respectively than those in the striatal region. CONCLUSIONS: The SBR before and after CSF area mask correction was associated with the ratio of the volume removed from the striatal and BG VOIs, and the SBR was high or low according to the ratio. The results suggest that CSF area mask correction is effective in patients with iNPH. TRIAL REGISTRATION: This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR) as UMIN study ID: UMIN000044826. 11/07/2021.

Serum MicroRNAs Predict Isolated Rapid Eye Movement Sleep Behavior Disorder and Lewy Body Diseases.

BACKGROUND: Isolated rapid eye movement sleep behavior disorder (IRBD) is a well-established clinical risk factor for Lewy body diseases (LBDs), such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). OBJECTIVE: To elucidate whether serum microRNA (miRNA) deregulation in IRBD can antedate the diagnosis of LBD by performing a longitudinal study in different progression stages of IRBD before and after LBD diagnosis and assessing the predictive performance of differentially expressed miRNAs by machine learning-based modeling. METHODS: Using genome-wide miRNA analysis and real-time quantitative polymerase chain reaction validation, we assessed serum miRNA profiles from patients with IRBD stratified by dopamine transporter (DaT) single-photon emission computed tomography into DaT-negative IRBD (n = 17) and DaT-positive IRBD (n = 21), IRBD phenoconverted into LBD (n = 13), and controls (n = 20). Longitudinally, we followed up the IRBD cohort by studying three time point serum samples over 26 months. RESULTS: We found sustained cross-sectional and longitudinal deregulation of 12 miRNAs across the RBD continuum, including DaT-negative IRBD, DaT-positive IRBD, and LBD phenoconverted IRBD (let-7c-5p, miR-19b-3p, miR-140, miR-22-3p, miR-221-3p, miR-24-3p, miR-25-3p, miR-29c-3p, miR-361-5p, miR-425-5p, miR-4505, and miR-451a) (false discovery rate P < 0.05). Age- and sex-adjusted predictive modeling based on the 12 differentially expressed miRNA biosignatures discriminated IRBD and PD or DLB from controls with an area under the curve of 98% (95% confidence interval: 89-99%). CONCLUSIONS: Besides clinical diagnosis of IRBD or imaging markers such as DaT single-photon emission computed tomography, specific miRNA biosignatures alone hold promise as progression biomarkers for patients with IRBD for predicting PD and DLB clinical outcomes. Further miRNA studies in other PD at-risk populations, such as LRRK2 mutation asymptomatic carriers or hyposmic subjects, are warranted. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dopamine transporter (DAT) imaging in Parkinson's disease and related disorders.

This review gives an insight into the beginnings of dopamine transporter (DAT) imaging in the early 1990s, focussing on single photon emission tomography (SPECT). The development of the method and its consolidation as a now widely used clinical tool is described. The role of DAT-SPECT in the diagnosis and differential diagnosis of PD, atypical parkinsonian syndromes and several other different neurological disorders is reviewed. Finally the clinical research using DAT-SPECT as a biomarker for the progression of PD, for the detection of a preclinical dopaminergic lesion and its correlation with neuropathological findings is outlined.

Aceruloplasminemia: a multimodal imaging study in an Italian family with a novel mutation.

OBJECTIVE: Structural abnormalities in thalami and basal ganglia, in particular the globus pallidus (GP), are a neuroimaging hallmark of hereditary aceruloplasminemia (HA), yet few functional imaging data exit in HA carriers. This study investigated the iron-related structural and functional abnormalities in an Italian HA family. METHODS: Multimodal imaging was used including structural 3 T MRI, functional imaging (SPECT imaging with 123I-ioflupane (DAT-SPECT), cardiac 123I metaiodobenzylguanidine (123I-MIBG) scintigraphy, and 18F-fluorodeoxyglucose (18F-FDG)-PET imaging). In the proband, MRI and scintigraphic evaluations were performed at baseline, 2 and 4 years (structural imaging), and 2 years of follow-up period (functional imaging). RESULTS: We investigated two cousins carrying a novel splicing homozygous mutation in intron 6 (IVS6 + 1 G > A) of CP gene. Interestingly, MRI features in both subjects were characterized by marked iron accumulation in the thalami and basal ganglia nuclei, while GP was not affected. MRI performed in the proband at 2 and 4 years of follow-up confirmed progressive neurodegeneration of the thalami and basal ganglia without the involvement of GP. Functional imaging showed reduced putaminal DAT uptake in both cousins, whereas cardiac MIBG and FDG uptakes performed in the proband were normal. Longitudinal scintigraphic investigations did not show significant changes over the time. CONCLUSIONS: For HA carriers, our findings demonstrate that GP was spared by iron accumulation over the time. The nigrostriatal presynaptic dopaminergic system was damaged while the cardiac sympathetic system remained longitudinally preserved, thus expanding the imaging features of this rare inherited disorder.

Asymmetric Dopamine Transporter Loss Affects Cognitive and Motor Progression in Parkinson's Disease.

BACKGROUND: Asymmetric hemispheric loss of dopaminergic neurons is one of the characteristic features of Parkinson's disease (PD). However, it is still debated if right or left asymmetry differently affects cognitive and motor progression. OBJECTIVES: The objective of this study was to investigate, for the first time, the relevance of dopamine transporter (DAT) asymmetry on cognitive and motor manifestations at onset and at 4-year progression in drug-naïve PD. METHODS: From the Parkinson's Progression Markers Initiative multicenter cohort, we identified 249 right-handed patients with PD with baseline asymmetry greater than 20% in putamen DAT binding at single-photon emission computed tomography. A predominant putamen asymmetry was found on the left in 143 patients (PD-left), and on the right side in 106 patients (PD-right); we compared them with 196 healthy controls. Patients were followed longitudinally (2-year and 4-year visits), examining their clinical, cognitive, and imaging data. RESULTS: At baseline, the PD-left group showed worse performance on the Symbol Digit Modality Test, an attention and processing-speed test, and lower cerebrospinal fluid ß-amyloid levels than the PD-right group. These differences were maintained at follow-up, declining over time in both groups. By contrast, the PD-right group showed greater motor impairment at baseline, which increased over 4 years. Striatal DAT binding decreased over time in both groups, but the PD-right group showed a steeper decline, particularly during the first 2-year follow-up. Putaminal asymmetry assessed at baseline was maintained over time. CONCLUSIONS: These findings suggest that hemispheric asymmetric dopaminergic denervation influences PD cognitive and motor performance as well as progression. Predominant right hemisphere nigrostriatal dopaminergic loss is associated with greater motor severity, whereas more pronounced left hemisphere denervation affects cognitive manifestations at onset and their progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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

BACKGROUND: 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 8 years. METHODS: 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. RESULTS: 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. CONCLUSIONS: The rate of conversion to PD at 8 years in this cohort aged ~58 years 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.

Diagnostic accuracy of DAT-SPECT and MIBG scintigraphy for dementia with Lewy bodies: an updated systematic review and Bayesian latent class model meta-analysis.

PURPOSE: Imperfect clinical reference standards can preclude accurately estimating the diagnostic accuracy of DAT-SPECT and MIBG myocardial scintigraphy for diagnosing DLB. To investigate the validity of unadjusted accuracy, we updated our previous meta-analysis. METHODS: Literature search was updated to March 18, 2018. We also examined published systematic review reports. Two investigators extracted data and rated study validity using the QUADAS-2 tool. We performed a Bayesian latent class model meta-analysis accounting for imperfect reference standards. RESULTS: We evaluated 27 studies including 2236 patients. With the exception of two DAT-SPECT studies that involved postmortem neuropathological verification, studies were susceptible to bias from imperfect reference standards. Compared with the unadjusted accuracy estimates, the adjusted sensitivity values were similar, whereas the adjusted specificity values were generally lower for detecting α-synuclein pathology in the brain. The adjusted summary sensitivity and specificity were 0.86 (95% credible interval [CrI], 0.76-0.95) and 0.81 (CrI, 0.70-0.92), and 0.93 (CrI, 0.74-1.00) and 0.75 (CI, 0.47-0.94) for visual and semi-quantitative assessments of DAT-SPECT, respectively; 0.92 (CrI, 0.81-0.99) and 0.80 (CrI, 0.67-0.93), and 0.87 (CrI, 0.74-0.98) and 0.80 (CrI, 0.69-0.93), for delayed- and early-phase scans of MIBG scintigraphy, respectively. When diagnosing the typical clinical syndrome, the adjusted accuracy values were similar to the unadjusted estimates. The adjusted sensitivity and specificity were 0.89 (CrI, 0.75-0.98) and 0.87 (CrI, 0.72-0.97), and 0.97 (CrI, 0.78-1.0) and 0.70 (CrI, 0.43-0.92) for visual and semi-quantitative assessments of DAT-SPECT, respectively; and 0.93 (CrI, 0.81-0.98) and 0.90 (CrI, 0.73-0.97), and 0.85 (CrI, 0.66-0.96) and 0.96 (95% CI, 0.83-1.0) for delayed- and early-phase scans of MIBG scintigraphy, respectively. CONCLUSIONS: In our adjusted analyses, both imaging biomarkers had high diagnostic accuracy for detecting the hallmark pathology in the brain and for diagnosing the typical clinical syndrome.

Early detection of cognitive impairment in Parkinson's disease with the use of the Wisconsin Card Sorting Test: correlations with Montreal Cognitive Assessment and smell identification test.

Cognitive function is often impaired in early Parkinson's disease (PD). The Wisconsin Card Sorting Test (WCST) is a neuropsychological test of "set-shifting" ability. To see whether WCST is useful for detecting early changes of cognitive function in PD, we examined the correlations of WCST with the Montreal Cognitive Assessment (MoCA) and the Odor Stick Identification Test (OSIT). Subjects were 48 PD patients (age 66 ± 10 years; Hoehn & Yahr stage 2.3 ± 0.8; mean duration 3.1 ± 2.5 years). WCST sub-scores for categories achieved (CA), perseverative errors of Nelson type (PEN), and difficulties of maintaining set (DMS) were evaluated. MoCA-J (Japanese version) and OSIT-J (Japanese version) were done in that order, followed by the WCST. In PD patients, CA was 2.2 ± 2.0, PEN was 7.0 ± 6.4, and DMS was 2.3 ± 2.0, and all were worse than those of age-matched normal subjects. MoCA-J scores significantly correlated with PEN. OSIT-J scores were also significantly correlated with CA and DMS. As MoCA-J and OSIT-J show high sensitivity and specificity for detecting mild cognitive impairment in PD, WCST may also be a useful supplementary diagnostic tool for early and mild cognitive impairment in PD patients.

[Development of a Striatal and Skull Phantom for Quantitative 123I-FP-CIT SPECT].

BACKGROUND: 123Iodine-labelled N-(3-fluoropropyl) -2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane (123I-FP-CIT) single photon emission computerized tomography (SPECT) images are used for differential diagnosis such as Parkinson's disease (PD). Specific binding ratio (SBR) is affected by scattering and attenuation in SPECT imaging, because gender and age lead to changes in skull density. It is necessary to clarify and correct the influence of the phantom simulating the the skull. PURPOSE: The purpose of this study was to develop phantoms that can evaluate scattering and attenuation correction. METHODS: Skull phantoms were prepared based on the measuring the results of the average computed tomography (CT) value, average skull thickness of 12 males and 16 females. 123I-FP-CIT SPECT imaging of striatal phantom was performed with these skull phantoms, which reproduced normal and PD. SPECT images, were reconstructed with scattering and attenuation correction. SBR with partial volume effect corrected (SBRact) and conventional SBR (SBRBolt) were measured and compared. RESULTS: The striatum and the skull phantoms along with 123I-FP-CIT were able to reproduce the normal accumulation and disease state of PD and further those reproduced the influence of skull density on SPECT imaging. The error rate with the true SBR, SBRact was much smaller than SBRBolt. CONCLUSION: The effect on SBR could be corrected by scattering and attenuation correction even if the skull density changes with 123I-FP-CIT on SPECT imaging. The combination of triple energy window method and CT-attenuation correction method would be the best correction method for SBRact.

123I-FP-CIT SPECT imaging in blepharospasm.

INTRODUCTION: Blepharospasm is a focal dystonia characterized by involuntary cocontraction of the eyelid protractors, causing spasmodic closure of the eyelids. Apraxia of eyelid opening is caused by an inability to initiate lid opening without paralytic abnormality. Some studies suggest that patients with either pure blepharospasm or blepharospasm associated with apraxia of eyelid opening are more prone to developing Parkinson's disease. METHODS: In our study, 123I-FP-CIT (DAT) SPECT was performed in 24 patients with either pure blepharospasm or blepharospasm associated with apraxia of eyelid opening and no signs of parkinsonism to identify dopaminergic dysfunction. RESULTS: DAT-SPECT was abnormal in 11 (46%) cases (five patients with isolated blepharospasm and six patients with blepharospasm associated with apraxia of eyelid opening) whose mean disease duration was 11 years. CONCLUSION: Our study revealed presynaptic dopaminergic dysfunction, as determined by 123I-FP-CIT or DAT-SPECT, in nearly half of our blepharospasm patients (with or without apraxia of eyelid opening). Thus, the presence of blepharospasm might be an early sign of a parkinsonian syndrome.

Alterations of putaminal shape in de novo Parkinson's disease.

INTRODUCTION: Several neuroimaging studies have been carried out to gain insight on the pathological processes that cause PD, but literature findings are inconsistent. The aim of this study was to combine information carried by functional imaging with DA transporter ligands and structural MRI. METHODS: Forty-two untreated, de novo-PD patients and 30 control subjects were involved in this study. Patients were divided in subgroups according to the presence of uni- or bilateral reduction of ligand uptake in the putamen, as observed on DA transporter single-photon emission tomography: 12 patients had abnormal uptake in the right putamen and 11 in the left, whereas 19 had bilateral abnormal uptake. Voxel-based morphometry and shape analysis were used to compare healthy subjects to all de novo-PD or to patients with either right or left abnormal uptake. RESULTS: Shape analysis identified significant differences between de novo-PD and controls in putaminal regions. In patients with unilateral abnormal uptake, only the medial surface of the structure was involved. When patients with bilateral uptake reduction were also considered, changes extended from the medial to the lateral surface of putamina. Voxel-based morphometry showed similar results to those detected with shape analysis, but it failed to identify the putaminal subfield involved in patients with asymmetric or symmetric damage on DA transporter single-photon emission tomography. CONCLUSIONS: Shape analysis in de novo-PD patients suggested a progressive medial-to-lateral involvement of the putamina that paralleled an asymmetric-to-bilateral distribution of DA transporter depletion. © 2016 International Parkinson and Movement Disorder Society.

Reduced α-synuclein levels in cerebrospinal fluid in Parkinson's disease are unrelated to clinical and imaging measures of disease severity.

BACKGROUND AND PURPOSE: The cerebrospinal fluid (CSF) concentration of α-synuclein may reflect the aggregation of α-synuclein in brain tissue that neuropathologically characterizes Parkinson's disease (PD). Although most studies in large cohorts report reduced CSF α-synuclein levels in PD, the available data to date are not consistent due to variation in group sizes, pre-analytical confounding factors and assay characteristics. Furthermore, it remains unclear whether CSF α-synuclein concentrations correlate with measures of disease severity. Acknowledging the methodological issues that emerged from previous studies, we evaluated whether CSF α-synuclein levels differ between patients with PD and controls, and relate to disease duration or severity. METHODS: α-Synuclein levels were measured in CSF samples of 53 well-characterized patients with PD and 50 healthy controls employing a recently developed time-resolved Förster's resonance energy transfer assay. In addition, we studied the relationship of CSF α-synuclein levels with disease duration, clinical measures of disease severity and the striatal dopaminergic deficit as measured by dopamine transporter binding and single photon emission computed tomography. RESULTS: In patients with PD, we observed a decrease in mean CSF α-synuclein levels that was unrelated to disease duration or measures of disease severity. Using total protein normalized α-synuclein, a sensitivity and specificity of 70% and 74% could be reached for distinguishing between patients with PD and controls. CONCLUSION: CSF α-synuclein levels are reduced in patients with PD compared with healthy controls. However, sensitivity and specificity indicate that α-synuclein will not suffice as a single biomarker. CSF α-synuclein levels do not correlate with measures of disease severity, including striatal dopaminergic deficit.

Pseudo-Orthostatic Tremor in Graves' Disease: A Possible Early Sign of Parkinsonism?

Background: Pseudo-orthostatic tremor is a hyperkinetic movement disorder usually associated with other neurological comorbidities, mainly Parkinson's disease. Case report: A 65-year-old male presented with unsteadiness and leg tremor while standing. Electrophysiological evaluation confirmed the presence of pseudo-orthostatic tremor. Blood test showed an undiagnosed Graves' disease. A complete remission of tremor was achieved with methimazole. Dopamine transporter scintigraphy showed a mild reduction of the striatal binding, bilaterally. Discussion: Graves' disease can be associated with pseudo-orthostatic tremor. Thyroid function should be assessed in patients complaining of unsteadiness. The causative role of hyperthyroidism in determining dopaminergic degeneration and uncovering subclinical parkinsonism warrants further investigations.