PARK2 Patient Presenting with Dopa-Responsive Dystonia

We report a 34-year-old female PARK2 patient presenting with dopa-responsive dystonia (DRD). She noticed difficulty in raising her foot while walking at the age of 24. Her lower limb symptoms were identified as dystonia later, and she was started on Menesit, which resulted in improvement of her symptoms. She was diagnosed as DRD and has been on continuous treatment since then. The specific binding ratio (SBR) of ¹²³I FP-CIT SPECT was significantly lower than those of controls of the same age, but ¹²³I-meta-iodobenzylguanidine myocardial scintigraphy showed a normal heart to mediastinum ratio. The Montreal Cognitive Assessment, Japanese version, was normal for her age. DRD is an inherited dystonia that typically begins during childhood and may be caused by mutations of the GCH1 (GTP cyclohydrolase), SPR (sepiapterin reductase), or TH (tyrosine hydroxylase) genes. Our patient was diagnosed as PARK2, known as autosomal-recessive juvenile Parkinson’s disease, based on genetic analysis. Although there was no family history of the disease, the decrease in SBR of ¹²³I FP-CIT SPECT enabled us to diagnose PARK2 and to differentiate this from DRD due to other genetic disorders.

Imaging of the nigrostriatal system for evaluating the preclinical phase of Parkinson’s disease development: the utility of neuromelanin, diffusion MRI, and DAT-SPECT

Objectives: To assess the utility of examining the nigrostriatal system with magnetic resonance imaging (MRI) and dopamine transporter (DAT) imaging for evaluating the preclinical phase of Parkinson’s disease (PD). Methods: The subjects were 32 patients with early PD and a history of probable rapid eye movement sleep behavior disorder (RBD; PD group), 15 patients with idiopathic RBD (RBD group), and 24 age-matched healthy controls (HC group) who underwent neuromelanin and diffusion tensor MRI for analysis of the substantia nigra pars compacta (SNpc). The RBD and PD groups underwent DAT imaging. In the RBD group, totals of 39 MRI and 27 DAT imaging examinations were obtained longitudinally. For each value, intergroup differences and receiver-operating characteristic (ROC) analysis for diagnostic performance were examined statistically. Results: The neuromelanin value was significantly lower and the diffusion tensor values except fractional anisotropy were significantly higher in the RBD and PD groups than in the HC group. The DAT specific binding ratio (SBR) was significantly lower in the PD group than in the RBD group. The areas under the ROC curves (AUCs) for neuromelanin/mean diffusivity value in the SNpc were 0.76/0.82 for diagnosing RBD and 0.83/0.80 for diagnosing PD. The AUC for the SBR for discriminating PD from RBD was 0.87. Conclusions: MRI and DAT imaging may be useful for evaluating sequential nigrostriatal changes during the preclinical phase of PD. Advances in knowledge: MRI detects nigrostriatal changes in both RBD and early PD, and DAT imaging detects nigrostriatal changes during the transition to PD in RBD.

Effect of Cerebrospinal Fluid Area Mask Correction on 123I-FP-CIT SPECT Images in Idiopathic Normal Pressure Hydrocephalus

Cerebrospinal fluid (CSF) mask correction has been developed to reduce the influence by CSF area dilatation for 123I-FP-CIT accumulation. In this study, we assessed the effect of CSF mask correction on the specific binding ratio (SBR) for 25 patients with idiopathic normal pressure hydrocephalus (iNPH). The SBRs with and without CSF mask correction were calculated, and changes in quantitative values were verified. Additionally, the volume removed from striatal and background (BG) volume of interest (VOI) by the CSF mask correction was calculated, the volumes removed were compared to verify their effect on SBR. Twenty and five patients had low and high SBRs, respectively, after CSF mask correction. The images of 20 and 5 patients with SBRs that were decreased and increased, respectively, by CSF mask correction showed that the volumes removed from the BG region VOI were higher and lower, respectively, than those in the striatal region. In conclusion, the SBR before and after CSF 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 may indicate that CSF mask correction is effective in patients with iNPH. This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR) as UMIN study ID: UMIN000044826.

Asymmetric Dopaminergic Dysfunction in Brain-First versus Body-First Parkinson’s Disease Subtypes

Background: We have hypothesized that Parkinson’s disease (PD) comprises two subtypes. Brain-first, where pathogenic α-synuclein initially forms unilaterally in one hemisphere leading to asymmetric nigrostriatal degeneration, and body-first with initial enteric pathology, which spreads through overlapping vagal innervation leading to more symmetric brainstem involvement and hence more symmetric nigrostriatal degeneration. Isolated REM sleep behaviour disorder has been identified as a strong marker of the body-first type. Objective: To analyse striatal asymmetry in [18F]FDOPA PET and [123I]FP-CIT DaT SPECT data from iRBD patients, de novo PD patients with RBD (PD +RBD) and de novo PD patients without RBD (PD - RBD). These groups were defined as prodromal body-first, de novo body-first, and de novo brain-first, respectively. Methods: We included [18F]FDOPA PET scans from 21 iRBD patients, 11 de novo PD +RBD, 22 de novo PD - RBD, and 18 controls subjects. Also, [123I]FP-CIT DaT SPECT data from iRBD and de novo PD patients with unknown RBD status from the PPPMI dataset was analysed. Lowest putamen specific binding ratio and putamen asymmetry index (AI) was defined. Results: Nigrostriatal degeneration was significantly more symmetric in patients with RBD versus patients without RBD or with unknown RBD status in both FDOPA (p = 0.001) and DaT SPECT (p = 0.001) datasets. Conclusion: iRBD subjects and de novo PD +RBD patients present with significantly more symmetric nigrostriatal dopaminergic degeneration compared to de novo PD - RBD patients. The results support the hypothesis that body-first PD is characterized by more symmetric distribution most likely due to more symmetric propagation of pathogenic α-synuclein compared to brain-first PD.

Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability

Purpose The adenosine A2A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A2A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A2A receptor radiotracer and report herein the preclinical evaluation of [18F]FLUDA, a deuterated isotopologue of [18F]FESCH. Methods [18F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats. Results [18F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72–180 GBq/μmol. Autoradiography proved A2A receptor–specific accumulation of [18F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [18F]FLUDA compared to that of [18F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [18F]FLUDA towards striatal A2A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [18F]FLUDA. Conclusions The new radiotracer [18F]FLUDA is suitable to detect the availability of the A2A receptor in the brain with high target specificity. It is regarded ready for human application.

The Association of Visually Guided Saccades and DAT-SPECT Findings in Parkinson’s Disease

<b><i>Background:</i></b> In individuals with Parkinson’s disease (PD), visually guided saccades (VGSs) reportedly reflect general motor dysfunction and cognitive impairments. However, it has not been fully elucidated whether the VGS abnormalities result from nigrostriatal degeneration or other PD-related neural changes. <b><i>Methods:</i></b> We measured VGS latency and gain in 50 PD participants and 56 age-matched normal controls (NCs), and PD participants underwent dopamine transporter (DAT) single-photon emission computed tomography (SPECT) within 2 months of the measurement. VGSs were evoked by a white dot on a monitor, which was presented at the center and pseudo-randomly jumped off horizontally (10° or 20° eccentricity) or vertically (10° or 15°). First, we compared the parameters between PD participants and NCs for each target location. Second, in the participants who exhibited striatal DAT asymmetry on SPECT, VGSs contralaterally directed to the more severely affected striatum were compared with those ipsilaterally directed. Third, effects of the DAT-SPECT specific binding ratio (SBR) on VGSs were analyzed. <b><i>Results:</i></b> PD participants demonstrated prolonged latencies when the target was presented at the upward 15° eccentricity and decreased gains at all target locations. Contralateral VGSs relative to the side of the more severely affected striatum were more delayed and hypometric than ipsilateral. The SBR had a significant positive effect on VGS gain. <b><i>Conclusions:</i></b> In participants with PD, saccadic abnormalities were emphasized when VGSs were directed contralaterally to the more severely affected striatum. Moreover, the dopaminergic nigrostriatal degeneration on DAT-SPECT was mainly associated with VGS gain.

Impact of age and sex correction on the diagnostic performance of dopamine transporter SPECT

Purpose The specific binding ratio (SBR) of 123I-FP-CIT (FP-CIT) in the putamen decreases with age by about 5% per decade and most likely is about 10% higher in females. However, the clinical utility of age and sex correction of the SBR is still a matter of debate. This study tested the impact of age and sex correction on the diagnostic performance of the putamen SBR in three independent patient samples. Methods Research sample: 207 healthy controls (HC) and 438 Parkinson’s disease (PD) patients. Clinical sample A: 183 patients with neurodegenerative parkinsonian syndrome (PS) and 183 patients with non-neurodegenerative PS from one site. Clinical sample B: 84 patients with neurodegenerative PS and 38 patients with non-neurodegenerative PS from another site. Correction for age and sex of the putamen SBR was based on linear regression in the HC or non-neurodegenerative PS, separately in each sample. The area under the ROC curve (AUC) was used as performance measure. Results The putamen SBR was higher in females compared to males (PPMI: 14%, p < 0.0005; clinical sample A: 7%, p < 0.0005; clinical sample B: 6%, p = 0.361). Age-related decline of the putamen SBR ranged between 3.3 and 10.4% (p ≤ 0.019). In subjects ≥ 50 years, age and sex explained < 10% of SBR between-subjects variance. Correction of the putamen SBR for age and sex resulted in slightly decreased AUC in the PPMI sample (0.9955 versus 0.9969, p = 0.025) and in clinical sample A (0.9448 versus 0.9519, p = 0.057). There was a small, non-significant AUC increase in clinical sample B (0.9828 versus 0.9743, p = 0.232). Conclusion These findings do not support age and sex correction of the putaminal FP-CIT SBR in the diagnostic workup of parkinsonian syndromes. This most likely is explained by the fact that the proportion of between-subjects variance caused by age and sex is considerably below the symptom threshold of about 50% reduction in neurodegenerative PS.

Acute hypokinetic-rigid syndrome following SARS-CoV-2 infection

ObjectiveTo report a case of a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) who acutely developed a hypokinetic-rigid syndrome.MethodsPatient data were obtained from medical records from the Hospital Universitario 12 de Octubre in Madrid, Spain. [123I]-ioflupane dopamine transporter (DaT) SPECT images were acquired 4 hours after a single dose of 185 MBq of 123I-FP-CIT. Quantitative analysis was performed with DaTQUANT software providing the specific binding ratio and z score values of the striatum.ResultsWe report a previously healthy 58-year-old man who developed hyposmia, generalized myoclonus, fluctuating and transient changes in level of consciousness, opsoclonus, and an asymmetric hypokinetic-rigid syndrome with ocular abnormalities after a severe SARS–CoV-2 infection. DaT-SPECT confirmed a bilateral decrease in presynaptic dopamine uptake asymmetrically involving both putamina. Significant improvement in the parkinsonian symptoms was observed without any specific treatment.ConclusionThis case study provides clinical and functional neuroimaging evidence to support that SARS–CoV-2 can gain access to the CNS, affecting midbrain structures and leading to neurologic signs and symptoms.