Specific Binding Ratio Research Articles

Specific Binding Ratio Estimation of [123I]-FP-CIT SPECT Using Frontal Projection Image and Machine Learning.

This study aimed to develop a new convolutional neural network (CNN) method for estimating the specific binding ratio (SBR) from only frontal projection images in single-photon emission-computed tomography using [123I]ioflupane. We created five datasets to train two CNNs, LeNet and AlexNet: (1) 128FOV used a 0° projection image without preprocessing, (2) 40FOV used 0° projection images cropped to 40 × 40 pixels centered on the striatum, (3) 40FOV training data doubled by data augmentation (40FOV_DA, left-right reversal only), (4) 40FOVhalf, and (5) 40FOV_DAhalf, split into left and right (20 × 40) images of 40FOV and 40FOV_DA to separately evaluate the left and right SBR. The accuracy of the SBR estimation was assessed using the mean absolute error, root mean squared error, correlation coefficient, and slope. The 128FOV dataset had significantly larger absolute errors compared to all other datasets (p < 0. 05). The best correlation coefficient between the SBRs using SPECT images and those estimated from frontal projection images alone was 0.87. Clinical use of the new CNN method in this study was feasible for estimating the SBR with a small error rate using only the frontal projection images collected in a short time.

Stereotactical normalization with multiple templates representative of normal and Parkinson-typical reduction of striatal uptake improves the discriminative power of automatic semi-quantitative analysis in dopamine transporter SPECT

BackgroundThe specific binding ratio (SBR) of 123I-FP-CIT in the putamen is widely used to support the interpretation of dopamine transporter (DAT) SPECT. Automatic methods for computation of the putamen SBR often include stereotactical normalization of the individual DAT-SPECT image to an anatomical standard space. This study compared using a single 123I-FP-CIT template image as target for stereotactical normalization versus multiple templates representative of normal and different levels of Parkinson-typical reduction of striatal 123I-FP-CIT uptake.Methods1702 clinical 123I-FP-CIT SPECT images were stereotactically normalized (affine) to the anatomical space of the Montreal Neurological Institute (MNI) with SPM12 either using a single custom-made 123I-FP-CIT template representative of normal striatal uptake or using eight different templates representative of normal and different levels of Parkinson-typical reduction of striatal FP-CIT uptake with and without attenuation and scatter correction. In the latter case, SPM finds the linear combination of the multiple templates that best matches the patient’s image. The putamen SBR was obtained using hottest voxels analysis in large unilateral regions-of-interest predefined in MNI space. The histogram of the putamen SBR in the whole sample was fitted by the sum of two Gaussians. The power to differentiate between reduced and normal SBR was estimated by the effect size of the distance between the two Gaussians computed as the differences between their mean values scaled to their pooled standard deviation.ResultsThe effect size of the distance between the two Gaussians was 3.83 with the single template versus 3.96 with multiple templates for stereotactical normalization.ConclusionsMultiple templates representative of normal and different levels of Parkinson-typical reduction for stereotactical normalization of DAT-SPECT might provide improved separation between normal and reduced putamen SBR that could result in slightly improved power for the detection of nigrostriatal degeneration.

Nigrosome 1 visibility and its association with nigrostriatal dopaminergic loss in Parkinson's disease.

Nigrosome 1 (NG1), a small cluster of dopaminergic cells in the substantia nigra and visible in the susceptibility map-weighted magnetic resonance image (SMwI), is severely affected in Parkinson's disease (PD). However, the degree of nigrostriatal degeneration according to the visibility of NG1 has not yet been well elucidated. We consecutively recruited 138 PD and 78 non-neurodegenerative disease (non-ND) patients, who underwent both 18 F-FP-CIT positron emission tomography (PET) and SMwI. Three neurologists and one radiologist evaluated the visibility of NG1 in SMwI. The participants were thereby grouped into visible, intermediate, and non-visible groups. Nigrostriatal dopaminergic input was calculated using the specific binding ratio (SBR) of the 18 F-FP-CIT PET. We determined the threshold of regional SBR for discriminating NG1 visibility and the probability for NG1 visibility according to regional SBR. Visual rating of NG1 showed excellent interobserver agreements as well as high sensitivity and specificity to differentiate the PD group from the non-ND group. NG1 was visible in seven patients (5.1%) in the PD group, who had relatively short disease duration or less severe loss of striatal dopamine. The threshold of putaminal SBR reduction on the more affected side for the disappearance of NG1 was 45.5%, and the probability for NG1 visibility dropped to 50% after the reduction of putaminal SBR to 41% from the normal mean. Almost half loss of nigrostriatal dopaminergic input is required to dissipate the hyperintensity of NG1 on SMwI, suggesting its utility in diagnosing PD only after the onset of the motor symptoms.

Same same but different: dopamine transporter SPECT on scanners with CZT vs. NaI detectors

BackgroundThe aims of this study were to establish a normal database (NDB) for semiquantification of dopamine transporter (DAT) single-photon emission computed tomography (SPECT) with [123I]FP-CIT on a cadmium zinc telluride (CZT) camera, test the preexisting NaI-derived NDB for use in CZT scans, and compare the diagnostic findings in subjects imaged with a CZT scanner with either the preexisting NaI-based NDB or our newly defined CZT NDB.MethodsThe sample comprised 73 subjects with clinically uncertain parkinsonian syndrome (PS) who prospectively underwent [123I]FP-CIT SPECT on a CZT camera according to standard guidelines with identical acquisition and reconstruction protocols (DaTQUANT). Two experienced readers visually assessed the images and binarized the subjects into “non-neurodegenerative PS” and “neurodegenerative PS”. Twenty-five subjects from the “non-neurodegenerative PS” subgroup were randomly selected to establish a CZT NDB. The remaining 48 subjects were defined as “test group”. DaTQUANT was used to determine the specific binding ratio (SBR). For the test group, SBR values were transformed to z-scores for the putamen utilizing both the CZT NDB and the manufacturer-provided NaI-based NDB (GE NDB). A predefined fixed cut-off of -2 was used for dichotomization of z-scores to classify neurodegenerative and non-neurodegenerative PS. Performance of semiquantification using the two NDB to identify subjects with neurodegenerative PS was assessed in comparison with the visual rating. Furthermore, a randomized head-to-head comparison of both detector systems was performed semiquantitatively in a subset of 32 out of all 73 subjects.ResultsCompared to the visual rating as reference, semiquantification based on the dedicated CZT NDB led to fewer discordant ratings than the GE NDB in CZT scans (3 vs. 8 out of 48 subjects). This can be attributed to the putaminal z-scores being consistently higher with the GE NDB on a CZT camera (median absolute difference of 1.68), suggesting an optimal cut-off of -0.5 for the GE NDB instead of -2.0. Average binding ratios and z-scores were significantly lower in CZT compared to NaI data.ConclusionsUse of a dedicated, CZT-derived NDB is recommended in [123I]FP-CIT SPECT with a CZT camera since it improves agreement between semiquantification and visual assessment.

Correlations between cerebrospinal fluid homovanillic acid and dopamine transporter SPECT in degenerative parkinsonian syndromes

Both cerebrospinal fluid (CSF) homovanillic acid (HVA) and striatal dopamine transporter (DAT) binding on single-photon emission computed tomography (SPECT) reflect nigrostriatal dopaminergic function, but studies on the relationship between the two have been limited. It is also unknown whether the reported variance in striatal DAT binding among diseases reflects the pathophysiology or characteristics of the subjects. We included 70 patients with Parkinson’s disease (PD), 12 with progressive supranuclear palsy (PSP), 12 with multiple system atrophy, six with corticobasal syndrome, and nine with Alzheimer’s disease as disease control, who underwent both CSF analysis and 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (123I-ioflupane) SPECT. We evaluated the correlation between CSF HVA concentration and the specific binding ratio (SBR) of striatal DAT binding. We also compared the SBR for each diagnosis, controlling for CSF HVA concentration. The correlations between the two were significant in patients with PD (r = 0.34, p = 0.004) and PSP (r = 0.77, p = 0.004). The mean SBR value was the lowest in patients with PSP and was significantly lower in patients with PSP than in those with PD (p = 0.037) after adjusting for CSF HVA concentration. Our study demonstrates that striatal DAT binding correlates with CSF HVA concentration in both PD and PSP, and striatal DAT reduction would be more advanced in PSP than in PD at an equivalent dopamine level. Striatal DAT binding may correlate with dopamine levels in the brain. The pathophysiology of each diagnosis may explain this difference.

The Titrated Mannitol Improved Central [99mTc] Tc TRODAT-1 Uptake in an Animal Model-A Clinically Feasible Application.

[99mTc]Tc TRODAT-1 is a widely used single photon emission tomography (SPECT) radiopharmaceutical in Asian practice for early detection of central dopaminergic disorders. However, its imaging quality remains sub-optimal. To overcome this problem, mannitol, an osmotic agent was used to observe its effect on improving striatal [99mTc]Tc TRODAT-1 uptake in rat brain by titrated human dosages to investigate a clinically feasible way to improve human imaging quality. [99mTc]Tc TRODAT-1 synthesis and quality control were performed as described. Sprague-Dawley rats were used for this study. The animal in vivo nanoSPECT/CT and ex vivo autoradiography were employed to observe and verify the striatal [99mTc]Tc TRODAT-1 uptake in rat brains using clinically equivalent doses (i.e., 0, 1 and 2 mL groups, each n = 5) of mannitol (20% w/v, equivalent to 200 mg/mL) by an intravenous administration. Specific binding ratios (SBRs) were calculated to express the central striatal uptake in different experimental groups. In the NanoSPECT/CT imaging, the highest SBRs of striatal [99mTc]Tc TRODAT-1 were reached at 75-90 min post-injection. The averaged striatal SBRs were 0.85 ± 0.13 (2 mL normal saline, the control group), 0.94 ± 0.26 (1 mL mannitol group) and 1.36 ± 0.12 (2 mL mannitol group, p < 0.01 which were significantly different than the control as well as 1 mL mannitol groups (p < 0.05). The SBRs from ex vivo autoradiography also showed a comparable trend of the striatal [99mTc]Tc TRODAT-1 uptake in the 2 mL, 1 mL mannitol and the control groups (1.76 ± 0.52, 0.91 ± 0.29, and 0.21 ± 0.03, respectively, p < 0.05). No remarkable changes of vital signs were found in the mannitol groups and the controls. Pre-treated mannitol revealed a significant increase of the central striatal [99mTc]Tc TRODAT-1 uptake in a rat model which not only enabled us to perform pre-clinical studies of dopaminergic related disorders but also provided a potential way to further optimize image quality in clinical practice.

Striatal Subregion Analysis Associated with REM Sleep Behavior Disorder in Parkinson's Disease.

REM sleep behavior disorder (RBD) in Parkinson's disease (PD) is associated with characteristic clinical subtypes and prognosis. In addition, nigrostriatal pathway, the most vulnerable anatomical area in PD, formed neuronal network interplaying with cortical and subcortical structures, and which may cause PD clinical phenotype. We evaluated the regional selectivity of presynaptic striatal dopaminergic denervation associated with RBD in PD. We compared two groups (n = 16) of PD patients with and without RBD in terms of specific binding ratios (SBR) in subregions of the striatum, which were measured using positron emission tomography with 18F-FP-CIT. SBRs of the anterior and posterior caudate, ventral striatum, and posterior and ventral putamen regions were measured in more or less affected side, and right or left side, or bilateral sum of the striatum. Age, disease duration, and severity of parkinsonism were not significantly different between groups. Although group differences in all areas were not significant with multiple comparison corrections, SBR of the ventral striatum and anterior caudate in sum of both sides was significantly less in the RBD than in the non-RBD group without correction (p < 0.05). In the right anterior caudate and left ventral striatum, SBR was also lower in the RBD than in the non-RBD group without correction (p < 0.05). Attention function was impaired in the RBD group compared with the non-RBD group (p < 0.05). However, these statistical significances were not definite after correction of multiple comparisons (p > 0.05). There is a possibility that RBD in early PD may be associated with presynaptic dopaminergic denervation in the ventral striatum and anterior caudate, which may explain decreased attention in our RBD group. RBD in PD may imply a distinct pathological progression. However, further study using large numbers of participants or longitudinal observation is necessary for the statistical conclusion because of small sample size.

A case of non-fluent/agrammatic variant of primary progressive aphasia with logoclonia

We report a case of non-fluent/agrammatic variant of primary progressive aphasia in a 79-year-old right-handed man who was admitted with a 5-year history of non-fluent speech and apraxia of speech. He also presented with agrammatism and logoclonia (the meaningless repetition of the middle or final syllable of a word). Furthermore, brain MRI revealed atrophy of the bilateral frontal and temporal lobes, while N-isopropyl-p-123I-iodoamphetamine single-photon emission computed tomography (SPECT) revealed relative hypoperfusion in the right basal ganglia. In addition, dopamine transporter SPECT revealed a decrease in specific binding ratio values, indicating neural dopamine dysfunction, which led to his diagnosis of progressive non-fluent aphasia with logoclonia. Logoclonia is a severe linguistic dysfunction usually observed in the advanced stages of Alzheimer's disease. However, based on the clinical course and cerebrospinal fluid evaluation results, our patient did not show any features of Alzheimer's disease. Thus, logoclonia might be associated with lesions involving the basal ganglia, right hemisphere, and left frontotemporal lobe.

Assessment of different regions of interest-based methods for [99mTc]Tc DAT-SPECT quantification using an anthropomorphic striatal phantom

Background and aimsMolecular imaging of the dopamine transporters (DAT) provides valuable information about neurodegenerative diseases, such as Parkinson’s. This study assessed the accuracy and precision of DAT-SPECT quantification methods.MethodsTwenty-three DAT-SPECT images of a striatal phantom were acquired. The specific (caudate and putamen) and the non-specific (background activity) chambers were filled with [99mTc]Tc. Different specific-to-non-specific activity ratios (10, 9, 8, 7, 6, 5, 4, 3 and 2 to 1) and the specific binding ratio (SBR) were calculated. Five methods using ROIs were assessed: (a) Manual ROIs on SPECT images; (b) TwoBox and (c) ThreeBox methods and Volume of Interest (VOI) using structural images; (d) MRI and (e) CT. Accuracy was evaluated by the concordance correlation coefficient (CCC) and precision by Pearson’s coefficient and linear regression.ResultsThe SBR quantified in the specific and striatal chambers resulted in a CCC increase with a decrease in the nominal values. For lower SBR, MRI and CT showed higher CCCs when caudate (hbox {CCC}_{mathrm{MRI-CA}} = 0.89 e hbox {CCC}_{mathrm{CT-CA}} = 0.84) and putamen (hbox {CCC}_{mathrm{MRI-PU}} = 0.86 e hbox {CCC}_{mathrm{CT-PU}} = 0.82) were evaluated. For striatal assessments, the TwoBox method was the most accurate (hbox {CCC}_{mathrm{TWOBOX-ST}} = 0.95). High Pearson’s coefficients were found in the correlations between all methods.conclusionsAll five methods showed high precision even when applied to images with different activities. MRI and CT were the most accurate for assessing the caudate or putamen. To assess the striatal chamber and in the absence of structural information, the TwoBox method is advisable.

The glucocerebrosidase mutations and uric acid levels in Parkinson’s disease: A 3-years investigation of a potential biomarker”

BackgroundBlood uric acid level indicates an emerging biomarker in Parkinson's disease (PD). This study aimed to evaluate longitudinal uric acid levels among different kinds of glucocerebrosidase (GBA) mutations and to compare it among sporadic PD, genetic cohort Parkinson's disease (GENPD), genetic cohort unaffected (GENUN), and healthy control (HC) patients. MethodsWe conducted a study on 654 individuals from the Parkinson's progression markers initiative (PPMI) database. Baseline characteristics, uric acid levels, movement disorder society unified Parkinson's disease rating scale III (MDS-UPDRS III), Hoehn and Yahr Parkinson stage (H&Y stage), and DaT scan specific binding ratio (SBR) data were obtained. Different GBA mutations were collected and categorized into three groups. Longitudinal measurements of uric acid and MDS-UPDRS III score were evaluated during 3-years of follow-up. ResultGENPD cohort exhibited a greater MDS-UPDRS III score, H&Y stage, and lower SBR in the right caudate, left caudate, and right putamen compared to sporadic PD. Baseline uric acid level was similar among all groups and different GBA variants. After adjustment for age, sex, and body mass index, the uric acid level was significantly lower in the GENPD group than in HC during year 2 (P-value: 0.009). No significant longitudinal differences were detected for the MDS-UPDRS III score and three groups of GBA mutations. ConclusionThis is the first study to assess uric acid levels and MDS-UPDRS III scores among different GBA mutation variants within 3 years of follow-up. We found similar clinical characteristics among different subtypes of GBA mutations.

Tau and amyloid PET imaging with 18F‐PI‐2620 and 18F‐Florbetaben in patients with early‐onset dementia and healthy controls

AbstractBackgroundAbnormal deposits of tau protein and beta‐amyloid are the two fundamental pathological features of Alzheimer's disease (AD). The research framework for AD diagnosis proposes categorizing subjects based on biomarker evidence of pathology using the ATN classification system (amyloid, tau, neurodegeneration). In‐vivo detection of amyloid pathology using positron emission tomography (PET) is well established and new generation tau PET tracers like 18F‐PI‐2620 have shown a high binding affinity for aggregated tau without significant off‐target binding. The purpose of this study is to describe the ability of 18F‐PI‐2620 to detect tau pathology in patients with early‐onset dementia (EOD) with proven amyloid pathology.MethodTen patients with EOD and positive 18F‐Florbetaben amyloid PET (age range 54‐64y, 8 with suspected early‐onset AD (EOAD) and 2 with logopenic variant primary progressive aphasia (lvPPA)), along with 14 healthy controls (HC) (age range 54‐76y) underwent dynamic PET scans for 75 minutes after injection of 18F‐PI‐2620 to examine the presence of tau‐pathology in cortical and deep brain regions. Specific binding ratios were derived from averaged PET images from 45‐75 min post‐injection.ResultIn 9 out of 10 EOD patients, 18F‐PI‐2620 uptake was robust and extensive predominantly in cortical regions with relative sparing of deep brain regions. In the remaining EOD case, binding was low but with the same distribution pattern described for other EOD patients. In one HC, significant, specific uptake was observed predominantly in deep brain regions. 18F‐PI‐2620 administration was safe and well‐tolerated.ConclusionOur preliminary results suggest an excellent performance of the tracer 18F‐PI‐2620 to detect tau deposits in EOAD and lvPPA. Tau PET imaging with 18F‐PI‐2620, in conjunction with 18F‐Florbetaben amyloid PET, distinctly discriminates between early‐onset dementias due to AD pathology from HC. These results also support the usefulness of 18F‐PI‐2620 for visualizing tau aggregation in EOD. Finally, 18F‐Florbetaben and 18F‐PI‐2620 appear to be reliable tools for establishing the ATN biomarker status in EOD patients. Nevertheless, further studies are needed to confirm these preliminary results.

Tau PET imaging with 18F‐PI‐2620 in patients with corticobasal syndrome: a case series

AbstractBackgroundCorticobasal syndrome (CBS) is the clinical phenotype originally described for corticobasal degeneration (CBD), a rare sporadic neurodegenerative 4‐repeat tauopathy, clinically characterized by the presence of asymmetric parkinsonism, apraxia, cortical sensory deficits, dystonia, myoclonus, and cognitive dysfunction. However, patients with CBS can have neurodegenerative pathology other than CBD, like progressive supranuclear palsy (PSP), Alzheimer's Disease (AD), Vascular Dementia, and Lewy body dementia. Selective tau tracers have made it possible to detect the presence of abnormal tau deposits in vivo. 18F‐PI‐2620 is a tau‐specific positron emission tomography (PET) tracer with a high binding affinity for aggregated tau. This study aims to investigate the potential role of 18F‐PI‐2620 as a biomarker in patients with CBS.MethodFour participants with clinical features consistent with probable CBS according to the 2013 Armstrong diagnostic criteria underwent dynamic PET scans for 75 min after injection of 18F‐PI‐2620. Specific binding ratios were derived from averaged PET images from 45‐75 min post‐injection.ResultFirst two patients had robust increases in 18F‐PI‐2620 uptake in temporal, parietal, and occipital cortical regions with relative sparing of globus pallidus and putamen. In the third patient, 18F‐PI‐2620 uptake was observed in the globus pallidus and putamen with relative sparing of cortical regions. The fourth patient had low 18F‐PI‐2620 uptake localized in the globus pallidus, temporal, and parietal regions.ConclusionIn the first two patients, 18F‐PI‐2620 binding distribution resembles what was described for Alzheimer's disease. In the third patient, 18F‐PI‐2620 uptake pattern suggests PSP. In this particular case, we hypothesize the definitive diagnosis is PSP‐CBS, a rare clinical presentation of PSP with CBS features. Finally, the fourth patient had low 18F‐PI‐2620 uptake but in areas clearly related to AD, PSP, and probably CBD. Our findings support CBS's heterogeneous pathological basis and suggest that 18F‐PI‐2620 could represent a valuable tool in the assessment of CBS, establishing an underlying tauopathy in most cases. However, we suspect 18F‐PI‐2620 in CBS is insufficient to distinguish, in some cases, AD pathology from other tauopathies. Therefore, the use of additional biomarkers to establish the presence of amyloid pathology should be considered. Further studies are needed to confirm these preliminary results.

Regional cortical hypoperfusion and atrophy correlate with striatal dopaminergic loss in Parkinson's disease: a study using arterial spin labeling MR perfusion.

To investigate the relationship of the striatal dopamine transporter density to changes in the gray matter (GM) volume and cerebral perfusion in patients with Parkinson's disease (PD). We evaluated the regional cerebral blood flow (CBF) and GM volume, concurrently measured using arterial spin labeling and T1-weighted magnetic resonance imaging, respectively, as well as the striatal specific binding ratio (SBR) in 123I-N-ω-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)nortropane (123I-FP-CIT) single-photon emission computed tomography in 30 non-demented patients with PD (15 men and 15 women; mean age, 67.2 ± 8.8years; mean Hoehn-Yahr stage, 2.2 ± 0.9). Voxel-wise regression analyses using statistical parametric mapping (SPM) were performed to explore the brain regions that showed correlations of the striatal SBR to the GM volume and CBF, respectively, with a height threshold of p < 0.0005 at the voxel level and p < 0.05 family-wise error-corrected at the cluster level. SPM analysis showed a significant positive correlation between the SBR and GM volume in the inferior frontal gyrus (IFG). Whereas, a positive correlation between the SBR and CBF was widely found in the frontotemporal and parietotemporal regions, including the IFG. Notably, the opercular part of the IFG showed significant correlations in both SPM analyses of the GM volume (r2 = 0.90, p < 0.0001) and CBF (r2 = 0.88, p < 0.0001). The voxel-wise analyses revealed the brain regions, mainly the IFG, that showed hypoperfusion and atrophy related to dopaminergic loss, which suggests that the progression of dopaminergic neurodegeneration leads to regional cortical dysfunction in PD.

Neuromelanin and T2*-MRI for the assessment of genetically at-risk, prodromal, and symptomatic Parkinson’s disease

MRI was suggested as a promising method for the diagnosis and assessment of Parkinson’s Disease (PD). We aimed to assess the sensitivity of neuromelanin-MRI and T2* with radiomics analysis for detecting PD, identifying individuals at risk, and evaluating genotype-related differences. Patients with PD and non-manifesting (NM) participants [NM-carriers (NMC) and NM-non-carriers (NMNC)], underwent MRI and DAT-SPECT. Imaging-based metrics included 48 neuromelanin and T2* radiomics features and DAT-SPECT specific-binding-ratios (SBR), were extracted from several brain regions. Imaging values were assessed for their correlations with age, differences between groups, and correlations with the MDS-likelihood-ratio (LR) score. Several machine learning classifiers were evaluated for group classification. A total of 127 participants were included: 46 patients with PD (62.3 ± 10.0 years) [15:LRRK2-PD, 16:GBA-PD, and 15:idiopathic-PD (iPD)], 47 NMC (51.5 ± 8.3 years) [24:LRRK2-NMC and 23:GBA-NMC], and 34 NMNC (53.5 ± 10.6 years). No significant correlations were detected between imaging parameters and age. Thirteen MRI-based parameters and radiomics features demonstrated significant differences between PD and NMNC groups. Support-Vector-Machine (SVM) classifier achieved the highest performance (AUC = 0.77). Significant correlations were detected between LR scores and two radiomic features. The classifier successfully identified two out of three NMC who converted to PD. Genotype-related differences were detected based on radiomic features. SBR values showed high sensitivity in all analyses. In conclusion, neuromelanin and T2* MRI demonstrated differences between groups and can be used for the assessment of individuals at-risk in cases when DAT-SPECT can’t be performed. Combining neuromelanin and T2*-MRI provides insights into the pathophysiology underlying PD, and suggests that iron accumulation precedes neuromelanin depletion during the prodromal phase.

Relationship between 123I-FP-CIT-SPECT and gait impairments in drug-naïve individuals with Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of nigrostriatal dopaminergic neurons [1]. In addition to cardinal motor symptoms, individuals with PD suffer of gait impairment [2]. Although functional imaging is useful for the diagnosis and pathophysiological evaluation of PD, little is known about the relationship between neuroimaging findings and PD clinical features. A study found a correlation between dopamine denervation and impaired gait automaticity [3]; others reported no association between dopaminergic denervation and some gait parameters, such as stride length and velocity [4,5], assuming that deficits in nondopaminergic neurotransmitter systems played the main role in gait impairments [3]. We aimed to examine the relationship between striatal dopaminergic depletion with disease severity in motor symptoms and gait variables in drug-naïve individuals with PD, in order to find where nigrostriatal pathway mainly acts. A total of 18 drug-naïve individuals with PD (mean age 70.4 ± 7.4 yrs) were enrolled. Motor symptoms were evaluated using the modified Hoehn and Yahr (H&Y) stage. Seven spatiotemporal variables of gait were acquired using a GAITRite® electronic walkway under comfortable walking, of which the coefficient of variation and the asymmetry were then calculated. The extent of striatal dopaminergic depletion was evaluated by dopamine transporter imaging with single-photon emission computed tomography using 123I-FP-CIT. Correlations between H&Y stage and gait variables with the specific binding ratios (SBRs) of the striatum (separated into putamen and caudate nucleus) were assessed with the Spearman's correlation coefficients (r). The mean SBRs of both the putamen and the caudate nucleus were significantly associated with the modified H&Y stage, with correlation coefficient of at least 0.60. A moderate correlation was found also between the asymmetry in the SBR of the putamen and the H&Y stage. Moreover, among the spatiotemporal gait variables, a moderate correlation was found between the mean double support duration and its asymmetry with the mean SBRs of both the putamen and the caudate nucleus (Table 1). On the contrary, stride length and velocity showed a weak correlation (below 0.30). Our findings suggest that both disease severity and gait impairments in early PD are associated with decreased dopamine binding in the striatum. Since the double support time showed a moderate correlation with dopaminergic depletion in particular in caudate nucleus, we propose this variable as a marker of the effect of nigrostriatal denervation on gait in individuals with early PD. On the other hand, the poor correlations found between the reduction of stride length and velocity with the nigrostriatal depletion confirmed the hypothesis of a major involvement of other systems (such as the cholinergic) in the control of these variables. Our findings supported the notion that a large part of gait impairments in PD resulted from multisystem degeneration [6,7].

Serial changes of I-123 FP-CIT SPECT binding asymmetry in Parkinson's disease: Analysis of the PPMI data.

BackgroundDopaminergic denervation and motor symptoms are usually asymmetric at the onset of Parkinson's disease (PD). In this study, we estimated the asymmetry of specific binding ratio (SBR) of I-123 FP-CIT SPECT images during 4-years of follow up, to demonstrate the pattern of serial changes of asymmetry.MethodsClinical and I-123 FP-CIT SPECT image data of 301 PD patients and 141 normal controls were reviewed from the Parkinson's Progression Markers Initiative cohort. I-123 FP-CIT SPECT images were taken at baseline, 1-, 2-, and 4-year follow up periods for PD patients, and at baseline for normal controls. Asymmetry index were calculated by two methods. Method 1, by using the ratio of absolute difference of right and left SBRs to the average SBR. Method 2, by using the ratio of absolute difference of right and left SBRs to the SBR values of age-matched normal controls.ResultsAsymmetry index by method 2 revealed a more significant decrease during the 4-year follow up period, compared with method 1. The baseline asymmetry index of the putamen by method 2 showed significant correlation with the non-dominant putamen SBRs. However, there were no significant correlation with the baseline asymmetry index by method 2 and motor symptoms, cognition, nor autonomic symptoms.ConclusionWe suggest a novel asymmetry index in association to age-matched normal SBR values. This novel index could be adopted in predicting and evaluating the natural course of PD.

Temporal trajectory model for dopaminergic input to the striatal subregions in Parkinson's disease

IntroductionAlmost half of the nigral neurons are already lost during the preclinical period of Parkinson's disease (PD), and then the speed of neuronal loss is slowly attenuated during the subsequent progression. We sought to establish long-term temporal trajectory models for the dopaminergic input to the striatal subregions and a 4D-temporal trajectory model for the dopamine transporter positron emission tomography (PET). MethodsWe selected 83 patients in PD spectrum who underwent dopamine transporter PET scan twice and 71 age-matched healthy controls. We created temporal trajectories of specific binding ratios of the striatal subregions by integrating function between baseline values and their annual change rates and also created 4D-temporal trajectory model by applying the same method for each striatal voxel. Using the PET data of additional 100 PD patients, we estimated an individual time point in the 4D-temporal trajectory model for the validation. ResultsDegenerative loss of striatal dopaminergic input first appeared in the posterior dorsal putamen in the more affected side at 14.4 years before the clinical onset, and subsequently in the posterior ventral and anterior putamen, and finally in the caudate. The time delay between the initiation of dopaminergic loss in the more and less affected posterior dorsal putamen was 6.1 years. The estimated individual time points within the entire disease course were correlated with the motor severity. ConclusionOur temporal trajectory model demonstrated a sequential loss of dopaminergic input in the striatal subregions in PD and may be beneficial for the evaluation of individual status of disease progression.

Statistical Considerations in the Design of Clinical Trials Targeting Prodromal Parkinson Disease.

Clinical trials testing interventions for prodromal Parkinson disease (PD) hold particular promise for preserving neuronal function and thereby slowing or even forestalling progression to overt PD. Selection of the appropriate target population and outcome measures presents challenges unique to prodromal PD. We propose 3 clinical trial designs, spanning phase 2a, phase 2b, and phase 3 development, that might serve as templates for prodromal PD trials. The proposed phase 2a trial is of a 3-arm design of short duration and focuses on proof of concept with respect to target engagement and change in a motor outcome in a subset of prodromal participants who already manifest asymptomatic but measurable motor dysfunction as an exploratory aim. The proposed phase 2b trial suggests progression of dopamine transporter imaging specific binding ratio as a primary outcome evaluated annually over 2 years with phenoconversion to PD as a key secondary outcome. The proposed phase 3 trial is a large, simple design of a nutraceutical or behavioral intervention with remote administration and phenoconversion as the primary outcome. We then consider what additional data are needed in the short term to better design prodromal PD trials and examine what longer-term goals would accelerate discovery of safe and effective therapies for individuals at risk of PD. Clear and potentially context-specific definitions of phenoconversion and validation of intermediate endpoints are needed in the short term. The use of adaptive trial designs, master protocols, and research registries would help accelerate therapy development in the long term.

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

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

Striatal Dopaminergic Depletion Pattern Reflects Pathological Brain Perfusion Changes in Lewy Body Diseases

PurposeIn Lewy body diseases (LBD), various symptoms occur depending on the distribution of Lewy body in the brain, and the findings of brain perfusion and dopamine transporter single-photon emission computed tomography (DAT-SPECT) also change accordingly. We aimed to evaluate the correlation between brain perfusion SPECT and quantitative indices calculated from DAT-SPECT in patients with LBD.ProceduresWe retrospectively enrolled 35 patients with LBD who underwent brain perfusion SPECT with N-isopropyl-p-[123I] iodoamphetamine and DAT-SPECT with 123I-ioflupane. Mini-mental state examination (MMSE) data were also collected from 19 patients. Quantitative indices (specific binding ratio [SBR], putamen-to-caudate ratio [PCR], and caudate-to-putamen ratio [CPR]) were calculated using DAT-SPECT. These data were analysed by the statistical parametric mapping procedure.ResultsIn patients with LBD, decreased PCR index correlated with hypoperfusion in the brainstem (medulla oblongata and midbrain) (uncorrected p < 0.001, k > 100), while decreased CPR index correlated with hypoperfusion in the right temporoparietal cortex (family-wise error corrected p < 0.05), right precuneus (uncorrected p < 0.001, k > 100), and bilateral temporal cortex (uncorrected p < 0.001, k > 100). However, there was no significant correlation between decreased SBR index and brain perfusion. Additionally, the MMSE score was correlated with hypoperfusion in the left temporoparietal cortex (uncorrected p < 0.001).ConclusionsThis study suggests that regional changes in striatal 123I-ioflupane accumulation on DAT-SPECT are related to brain perfusion changes in patients with LBD.