Automated assessment of the substantia nigra on susceptibility map-weighted imaging using deep convolutional neural networks for diagnosis of Idiopathic Parkinson's disease.

OBJECTIVES: Despite its use in determining nigrostriatal degeneration, the lack of a consistent interpretation of nigrosome 1 susceptibility map-weighted imaging (SMwI) limits its generalized applicability. To implement and evaluate a diagnostic algorithm based on convolutional neural networks for interpreting nigrosome 1 SMwI for determining nigrostriatal degeneration in idiopathic Parkinson's disease (IPD). METHODS: In this retrospective study, we enrolled 267 IPD patients and 160 control subjects (125 patients with drug-induced parkinsonism and 35 healthy subjects) at our institute, and 24 IPD patients and 27 control subjects at three other institutes on approval of the local institutional review boards. Dopamine transporter imaging served as the reference standard for the presence or absence of abnormalities of nigrosome 1 on SMwI. Diagnostic performance was compared between visual assessment by an experienced neuroradiologist and the developed deep learning-based diagnostic algorithm in both internal and external datasets using a bootstrapping method with 10000 re-samples by the "pROC" package of R (version 1.16.2). RESULTS: The area under the receiver operating characteristics curve (AUC) (95% confidence interval [CI]) per participant by the bootstrap method was not significantly different between visual assessment and the deep learning-based algorithm (internal validation, .9622 [0.8912-1.0000] versus 0.9534 [0.8779-0.9956], P = .1511; external validation, 0.9367 [0.8843-0.9802] versus 0.9208 [0.8634-0.9693], P = .6267), indicative of a comparable performance to visual assessment. CONCLUSIONS: Our deep learning-based algorithm for assessing abnormalities of nigrosome 1 on SMwI was found to have a comparable performance to that of an experienced neuroradiologist.

The pattern of FP-CIT PET in pure white matter hyperintensities-related vascular parkinsonism.

OBJECTIVES: To determine whether vascular parkinsonism (VaP) patients with visually normal dopamine transporter (DAT) scans have presynaptic dopaminergic depletion. METHODS: We enrolled 23 VaP patients who had parkinsonism, relevant diffuse subcortical white matter hyperintensities (WMH), and visually normal DAT scans, 23 Parkinson's disease (PD) patients, and 31 control subjects. By quantitatively analyzing 18F-N-(3-fluoropropyl)-2ß-carbon ethoxy-3ß-(4-iodophenyl) nortropane (18F-FP-CIT) positron emission tomography, we compared the pattern of striatal DAT availability among groups. The discriminatory power of striatal DAT availability to differentiate VaP patients from control subjects or PD patients was assessed using receiver operating characteristics (ROC) analyses. Additionally, correlation analysis was performed to determine whether WMH severity or Unified Parkinson Disease Rating Scale Part III (UPDRS-III) score is related to presynaptic dopaminergic depletion in VaP. RESULTS: VaP patients exhibited decreased DAT availability in all striatal subregions, including posterior putamen, compared to control subjects. VaP patients and control subjects had similar patterns of anteroposterior and ventrodorsal DAT gradients in caudate and putamen level, but VaP patients exhibited significantly different patterns at putamen level, relative to PD patients. The severity of periventricular WMH was significantly correlated with all substriatal DAT availability in VaP, but not with UPDRS-III scores. The ROC analysis showed that DAT availability in caudate and posterior putamen had a fair discriminatory power when differentiating VaP patients from control subjects. CONCLUSIONS: This study demonstrates that VaP patients with WMH exhibited diffusely decreased DAT availability without any specific regional gradients of DAT patterns distinct from either control subjects or PD patients.

A Case of Pregabalin-Induced Parkinsonism.

Drug-induced parkinsonism is the second common movement disorder after Parkinson's disease. It occurs due to the use of not only neuroleptics but also some other medications as pregabalin. Pregabalin is an antiepileptic drug and a structural analog of gamma-aminobutyric acid (GABA), and its use decreases the release of several neurotransmitters. In this case report, we present a 53-year-old female patient with the signs of parkinsonism following pregabalin treatment. Drug-induced parkinsonism was diagnosed based on the clinical features, investigations, and resolution of the complaints. The symptoms relieved after the treatment stopped at a follow-up of 10 days. Due to the rare report of pregabalin-induced parkinsonism, we aim to enhance clinicians' awareness of pregabalin's probable side effects.

Case Report: Dengue Virus-Triggered Parkinsonism in an Adolescent.

Dengue fever continues to be an important cause of morbidity and mortality in tropical and subtropical countries. A wide range of neurological manifestations including dengue encephalopathy, Guillain-Barre syndrome, acute disseminated encephalomyelitis, transverse myelitis, cranial nerve palsies, and myositis have been reported following dengue infection. But parkinsonism secondary to dengue virus infection is uncommon, with only three published case reports in adults and one in children. We describe a 13-year-old pre-morbidly normal boy, who presented with bradykinesia, bradyphonia, mask-like facies, and cogwheel rigidity while recovering from uncomplicated DF. He responded favorably to levodopa/carbidopa supplementation and had resolution of symptoms over the next 2 weeks. We also did a comparative review of all published cases of dengue-induced parkinsonism. Post-dengue, parkinsonism is uncommon, and treating clinicians should be aware of this uncommon but treatable neurological complication of a common arboviral infection.

Impaired functional connectivity of sensorimotor network predicts recovery in drug-induced parkinsonism.

OBJECTIVE: In a substantial portion of patients with drug-induced parkinsonism (DIP), parkinsonism may persist for long periods after discontinuation of offending drugs, suggesting subtle underlying neurodegeneration. We hypothesized that patients with DIP have impaired functional connectivity (FC) of brain networks, which may determine the reversibility of parkinsonism. METHODS: In this case-control study, we consecutively recruited 60 patients with DIP and 32 healthy controls. We used independent component analysis and dual regression of functional magnetic resonance imaging data to identify seven resting-state networks and compared FC of the networks between the DIP and control groups. Among regions where the two groups showed a significant difference in the FC with sensorimotor network, we compared the FC between patients who had completely recovered (n = 21) and those who had partially recovered (n = 39) within 3 months of cessation of the offending drugs. RESULTS: Patients with DIP had decreased FC between the sensorimotor network and widespread brain regions, when compared to healthy controls. FC in the prefrontal regions was negatively correlated with parkinsonian motor score. Patients who partially recovered had a significantly lower FC in the prefrontal and cerebellar regions than those who recovered completely, providing a useful predictor of recovery status. CONCLUSIONS: Patients with DIP had decreased FC of the sensorimotor network, which correlated with the severity of parkinsonism and predicted the recovery status after cessation of offending drugs. Impaired FC of the sensorimotor network can be used as a biomarker to evaluate the severity and prognosis of DIP.

Drug induced parkinsonism: Symptomatic beyond 22 months.

We report 2 cases of drug induced Parkinsonism followed longitudinally that remained symptomatic 22 and 27 months after stopping causative agents with normal dopamine ioflupane iodine-123 (DaT) single-photon emission computed tomography (SPECT) scans at 8 and 16 months.

Vascular Parkinsonism by Infarctions at Different Locations on 18F-FP-CIT PET/CT.

Cerebral vascular lesions are integral to the diagnosis of vascular parkinsonism (VP). The VP, also referred to as lower body parkinsonism, is frequently caused by subcortical white matter lesions, but lesions at any levels of the nigro-striato-thalamo-cortical pathway can also cause VP, thus giving rise to various symptoms other than gait disturbance. Previous dopamine transporter imaging studies using SPECT showed heterogeneous patterns suggesting diverse contributing lesions to VP. Here we present 3 cases of VP demonstrated by F-FP-CIT PET/CT, visualizing vascular lesions at different levels between the midbrain and motor cortex. Distinctive clinical manifestations of them recapitulate the pathogenesis of VP.

Diffusion Kurtosis Imaging Detects Microstructural Changes in a Methamphetamine-Induced Mouse Model of Parkinson's Disease.

Methamphetamine (METH) abuse is known to increase the risk of Parkinson's disease (PD) due to its dopaminergic neurotoxicity. This is the rationale for the METH model of PD developed by toxic METH dosing (10 mg/kg four times every 2 h) which features robust neurodegeneration and typical motor impairment in mice. In this study, we used diffusion kurtosis imaging to reveal microstructural brain changes caused by METH-induced neurodegeneration. The METH-treated mice and saline-treated controls underwent diffusion kurtosis imaging scanning using the Bruker Avance 9.4 Tesla MRI system at two time-points: 5 days and 1 month to capture both early and late changes induced by METH. At 5 days, we found a decrease in kurtosis in substantia nigra, striatum and sensorimotor cortex, which is likely to indicate loss of DAergic neurons. At 1 month, we found an increase of kurtosis in striatum and sensorimotor cortex and hippocampus, which may reflect certain recovery processes. Furthermore, we performed tract-based spatial statistics analysis in the white matter and at 1 month, we observed increased kurtosis in ventral nucleus of the lateral lemniscus and some of the lateral thalamic nuclei. No changes were present at the early stage. This study confirms the ability of diffusion kurtosis imaging to detect microstructural pathological processes in both grey and white matter in the METH model of PD. The exact mechanisms underlying the kurtosis changes remain to be elucidated but kurtosis seems to be a valuable biomarker for tracking microstructural brain changes in PD and potentially other neurodegenerative disorders.

Drug-Induced Parkinsonism Manifesting as Gait Freezing in a Patient With Traumatic Brain Injury: A Case Report.

BACKGROUND: Among the neuropsychiatric complications commonly induced by traumatic brain injury (TBI), behavioral disorders, such as agitation and aggression, can hinder neurological recovery and deteriorate rehabilitation outcomes. Pharmacological treatment for behavioral disorders might be beneficial but could lead to drug-induced parkinsonism. We report a case of a patient with drug-induced parkinsonism manifested as freezing of gait after TBI, which improved with the cessation of the offending drugs and comprehensive rehabilitation. CASE PRESENTATION: A 35-year-old male patient left with a TBI after a car accident was referred to our hospital. He had been on many neuropsychiatric medications, including atypical antipsychotics, for his agitated behaviors. He could walk independently but showed freezing of gait at the initiation of his gait, when turning to the side, when reaching his destination, and passing through narrow corridors. Under the impression of drug-induced parkinsonism, we gradually tapered the patient off his neuropsychiatric medications. He also underwent comprehensive rehabilitation, including gait training under visual and auditory cues and balance training. Five weeks after admission to the hospital, the patient's freezing of gait improved, with disappearance of his hesitation at gait initiation and a decreased freezing duration while turning around. CONCLUSIONS: This is a rare report of drug-induced parkinsonism manifested as freezing of gait, which showed improvement after discontinuation of the causative drugs and subsequent rehabilitation.

The role of exposure to pesticides in the etiology of Parkinson's disease: a 18F-DOPA positron emission tomography study.

Susceptibility to Parkinson's disease (PD) is believed to involve an interaction between genetic and environmental factors. The role of pesticides as a risk factor of PD and neurodegeneration remains controversial. An asymmetric decrease in ligand uptake on 18F-DOPA positron emission tomography (PET), especially in the dorsal putamen, is a sensitive marker of PD. The aim of this study was to examine the pattern of ligand uptake on 18F-DOPA PET in patients with PD exposed or not exposed to pesticides. The main sample included 26 Israeli patients with PD, 13 who were exposed to pesticides and 13 who were not, matched for age and disease duration. All underwent 18F-DOPA PET imaging, and an asymmetry index of ligand uptake between the ipsilateral and contralateral caudate, putamen, and whole striatum was calculated. No significant between-group differences were found in demographic variables, clinical asymmetry index (P = 0.15), or asymmetry index of ligand uptake in the putamen (P = 0.84), caudate (P = 0.78) and striatum (P = 0.45). Comparison of the 18F-DOPA results of the Israeli cohort with those of 17 non-pesticide-exposed patients with PD from Austria yielded no significant differences, further validating our findings. Our observations suggest that although exposure to pesticides might be a risk factor for PD, it does not have an effect on the asymmetry pattern in the nigrostriatal system over non-exposure. We assume that once the disease process is initiated in pesticide-exposed patients, the pathogenic mechanism does not differ from that of idiopathic PD.

Pathophysiology of levodopa-induced dyskinesia: Insights from multimodal imaging and immunohistochemistry in non-human primates.

BACKGROUND: Dopaminergic and serotonergic degenerations alter pharmacological neurotransmission and structural markers in Parkinson's disease (PD). Alteration of diffusion measures in key brain regions depict MPTP/MDMA lesions in the monkey model of PD. Whether dopatherapy impacts such diffusion measures remains an open question. OBJECTIVES: The aim of this study was to investigate the consequences of l-DOPA treatment on diffusion alterations, PET imaging and immunohistochemical markers in MPTP/MDMA-intoxicated monkeys. METHODS: We acquired PET imaging and measures of mean diffusivity and fractional anisotropy longitudinally and correlated them with behavior and post-mortem fiber quantification. RESULTS: Severity of l-DOPA-induced dyskinesia was correlated to serotonin transporter radioligand binding increases in the ventral striatum and the anterior cingulate cortex and decreases of mean diffusivity in the ventral striatum. After lesion of serotonergic fibers by MDMA and the second l-DOPA period, diffusion measures were no more altered while the serotonergic binding still increased in all regions of interest, despite abolition of dyskinesia. Interestingly, in the anterior cingulate cortex, the SERT radioligand binding was negatively correlated to the number of SERT fibers. CONCLUSION: These results show that the increase of SERT radioligand binding is not systematically paralleled by an increase of SERT fibers and does not always reflect the presence of LID. More specifically, our study suggest that SERT increase may be underpinned by an increased density of serotonergic fibers after MPTP and the first l-DOPA period, and by an elevation of SERT itself after MDMA and the second l-DOPA period. This highlights that DTI is complementary to PET imaging to decipher pathophysiological mechanisms underlying l-DOPA-induced dyskinesia in a non-human primate model of PD.

DAT-SPECT imaging in cases of drug-induced parkinsonism in a specialty movement disorders practice.

OBJECTIVE: Compare clinical characteristics and outcomes in cases where DAT-SPECT imaging is used to distinguish Parkinson's disease from Drug-Induced Parkinsonsim. BACKGROUND: Clinical uncertainty in diagnosing Parkinson's disease is common when patients are on dopamine-blocking medications. DAT-SPECT imaging can improve diagnostic certainty but little data are available on clinical characteristics and outcomes associated with normal and abnormal scan results. METHODS: Retrospective chart review of patients seen at a movement disorders center between 2011 and 2017 where DAT-SPECT was ordered to distinguish Parkinson's disease from Drug-induced Parkinsonism. Descriptive statistics were calculated for variables of interest and compared by scan result. Chi-squared analyses was carried out for categorical variables and students' t-tests for continuous values. RESULTS: 51 patients met inclusion criteria with 36 normal scans and 15 abnormal scans. Those with greater than 2 cardinal manifestations (tremor, rigidity, akinesia, postural instability) were more likely to have an abnormal scan (63.89% vs 93.33%, p = 0.04). No other clinical characteristics assessed were associated with scan results. Atypical antipsychotics (aripiprazole 39.21%, olanzapine 31.37%) and mood stabilizers (valproic acid 33.33%, lithium 17.65%) were most commonly associated with suspected Drug-induced Parkinsonism cases. A post-scan change in management occurred in 41.18% of patients. 55.56% of patients with normal scans responded to changes in the offending medication, with 16.66% taking over 3 months to show improvement. CONCLUSIONS: Many DAT-SPECT scans at our institution are ordered to distinguish Parkinson's disease from Drug-induced Parkinsonism because clinical characteristics alone are unreliable. DAT-SPECT results lead to changes in management and the outcomes of these changes are consistent with scan results.

Dissociation of reward and effort sensitivity in methcathinone-induced Parkinsonism.

Methcathinone-induced Parkinsonism is a recently described extrapyramidal syndrome characterized by globus pallidus and substantia nigra lesions, which provides a unique model of basal ganglia dysfunction. We assessed motivated behaviour in this condition using a novel cost-benefit decision-making task, in which participants decided whether it was worth investing effort for reward. Patients showed a dissociation between reward and effort sensitivity, such that pallidonigral complex dysfunction caused them to become less sensitive to rewards, while normal sensitivity to effort costs was maintained.

Ultrasound-triggered effects of the microbubbles coupled to GDNF- and Nurr1-loaded PEGylated liposomes in a rat model of Parkinson's disease.

The purpose of this study was to investigate ultrasound-triggered effects of the glial cell line-derived neurotrophic factor (GDNF) + nuclear receptor-related factor 1 (Nurr1)-polyethylene glycol (PEG)ylated liposomes-coupled microbubbles (PLs-GDNF + Nurr1-MBs) on behavioral impairment and neuron loss in a rat model of Parkinson's disease (PD). The unloaded PEGylated liposomes-coupled microbubbles (PLs-MBs) were characterized for zeta potential, particle size, and concentration. 6-hydroxydopamine (6-OHDA) was used to establish the PD rat model. Rotational, climbing pole, and suspension tests were used to detect behavioral impairment. The immunohistochemical staining of tyrosine hydroxylase (TH) and dopamine transporter (DAT) was used to assess the neuron loss. Western blot and quantitative real-time PCR (qRT-PCR) analysis were used to measure the expression levels of GDNF and Nurr1. The particle size of PLs-MBs was gradually increased, while the concentration and absolute zeta potential were gradually decreased as the time prolongs. 6-OHDA increased amphetamine-induced rotations and loss of dopaminergic neurons as compared to sham group. Interestingly, PLs-GDNF-MBs or PLs-Nurr1-MBs decreased rotations and increased the TH and DAT immunoreactivity. Combined of both genes resulted in a robust reduction in the rotations and a greater increase of the dopaminergic neurons. The delivery of PLs-GDNF + Nurr1-MBs into the brains using magnetic resonance imaging (MRI)-guided focused ultrasound may be more efficacious for the treatment of PD than the single treatment.

Transcranial sonographic findings may predict prognosis of gastroprokinetic drug-induced parkinsonism.

BACKGROUND: Drug-induced parkinsonism (DIP) is one important cause of parkinsonism and a major cause of misleading diagnosis of Parkinson's disease (PD). DIP is caused by dopamine receptor blocking agents. Its symptoms will improve after withdrawal of offending drugs. However, parkinsonism does not regress in several individuals. It may persist or exacerbate despite drug withdrawal. Transcranial sonography (TCS) of the substantia nigra (SN) has been widely used to diagnose PD and differentiate parkinsonism types. The objective of this study was to investigate the value of early TCS findings for predicting clinical outcome of patients with newly diagnosed gastroprokinetic drug-induced parkinsonism after withdrawal of dopamine receptor blocking agents. METHODS: Fifty PD, 69 DIP, and 74 healthy controls were enrolled in this study. Patients with DIP were categorized into two subgroups: clinically improved after drug withdrawal (pure DIP) and clinically persistent or aggravated parkinsonism after drug withdrawal (unmasked PD). TCS was performed for all individuals to detect echogenicity in the SN. RESULTS: Transcranial sonographic SN echogenicity was significantly increased in PD while DIP and controls had similar SN echogenicity. In subgroup analysis of DIP, transcranial sonographic SN echogenicity was significantly increased in unmasked PD compared to that in pure DIP or healthy controls. CONCLUSIONS: SN echogenicity on TCS could be a useful tool to differentiate PD from DIP in clinical situations. Pure DIP and unmasked PD exhibited different SN echogenicity patterns. Early SN echogenicity findings on TCS could be used a biomarker to predict clinical prognosis of DIP.

Neurotoxicity of carbon monoxide targets caudate-mediated dopaminergic system.

The clinical features of parkinsonism in carbon monoxide (CO) intoxication have been associated with striatal-related neuronal networks. As parkinsonian and neuropsychiatric features are both related to presynaptic dopaminergic integrity, the aim of this study was to explore the clinical significance of 99mTcTRODAT-1 in grading neurobehavioral scores and parkinsonian severity in CO intoxication. We enrolled 64 patients with CO intoxication, including 29 with parkinsonism (parkinsonism[+] group) and 35 without (parkinsonism[-] group). All of the patients received 99mTcTRODAT-1 neuroimaging evaluations, comprehensive neurobehavioral tests and assessments of the severity of parkinsonism using Unified Parkinson's Disease Rating Scale (UPDRS)-part III motor score. Univariate and multivariate regression analyses were used to test the predictive factors and scores for a diagnosis of parkinsonism and its severity. The parkinsonism(+) group had significantly lower cognitive scores and higher neuropsychiatric total scores compared with the parkinsonism(-) group, both of which were independently related to the severity of parkinsonism. 99mTcTRODAT-1 regional caudate signals were correlated with tremors at rest, action or postural tremors of the hands, bradykinesia and hypokinesia, and visuospatial, verbal fluency, abstract thinking and digit backwards scores. Scores of the neurobehavioral tests and UPDRS items were highly correlated (p<0.01). Our results validated the initial hypothesis in that neurobehavioral deficits and parkinsonian symptoms were highly related. This association was independent of demographic factors and initial carboxyhemoglobin level. Within the presynaptic dopaminergic circuit, the clinical role of the caudate in mediating the clinical symptoms in CO intoxication may outweigh the putamen.