Dual-phase 18 F-FP-CIT positron emission tomography and cardiac 123 I-MIBG scintigraphy of Parkinson's disease patients with GBA mutations: evidence of the body-first type?

BACKGROUND AND PURPOSE: Parkinson's disease (PD) with glucocerebrosidase (GBA) gene mutation (GBA-PD) is known to show more rapid clinical progression than sporadic PD without GBA mutation (sPD). This study was performed to delineate the specific patterns of cortical hypoperfusion, dopamine transporter uptake and cardiac meta-iodobenzylguanidine (MIBG) uptake of GBA-PD in comparison to sPD. METHODS: Through next-generation sequencing analysis targeting 41 genes, a total of 16 GBA-PD and 24 sPD patients (sex, age matched) were enrolled in the study, and the clinical, dual-phase [18 F]-N-(3-fluoropropyl)-2ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane (1 8 F-FP-CIT) positron emission tomography (PET) and cardiac 123 I-MIBG scintigraphy results were compared between the two groups. RESULTS: The GBA-PD group had higher rates of rapid eye movement sleep behavior disorder, orthostatic hypotension and neuropsychiatric symptoms than the sPD group. Early-phase 18 F-FP-CIT PET showed significantly lower standard uptake value ratio on bilateral posterior parietal cortex (0.94 ± 0.05 vs. 1.02 ± 0.04, p = 0.011) and part of the occipital cortex (p < 0.05) in the GBA-PD group than the sPD group. In striatal dopamine transporter uptake, the regional standard uptake value ratio, asymmetry index and caudate-to-putamen ratio were similar between the two groups. The GBA-PD group had a lower heart-to-mediastinum uptake ratio in 123 I-MIBG scintigraphy than the sPD group. CONCLUSIONS: The GBA-PD patients showed decreased regional perfusion in the bilateral posterior parietal and occipital cortex. Cardiac sympathetic denervation and non-motor symptoms (orthostatic hypotension, rapid eye movement sleep behavior disorder) were more common in GBA-PD than sPD. These findings suggest that GBA-PD patients have more widespread peripheral (extranigral) α-synuclein accumulation, representing a body-first PD subtype.

Deep brain stimulation in Parkinson disease with valosin-containing protein gene mutation.

BACKGROUND AND PURPOSE: Mutations in the gene encoding valosin-containing protein (VCP) are related to myriad medical conditions, including familial amyotrophic lateral sclerosis, inclusion body myopathy, and frontotemporal dementia. There are several reports of a link between these mutations and early onset Parkinson disease (PD). CASE DESCRIPTION: We report a 53-year-old PD patient with VCP mutation who later developed motor complications, thus receiving subthalamic nucleus deep brain stimulation (DBS) at the age of 56 years. However, myopathy emerged 1.5 years after surgery. CONCLUSIONS: With the phenotype variability of VCP, DBS should be carefully evaluated, considering the possible unfavorable long-term outcomes due to other symptoms of this mutation.

Plasma neurofilament light chain level and orthostatic hypotension in early Parkinson's disease.

To delineate the impact of non-motor markers (REM sleep behavior disorder (RBD), orthostatic hypotension (OH), cardiac sympathetic denervation, hyposmia) on neuronal injury in early-stage Parkinson's disease (PD), we measured the plasma neurofilament light chain (NFL) level of PD patients and evaluated its relationship with these markers. The study population comprised a cohort of 77 patients with PD and 54 controls. OH was assessed using 5-min head-up tilt-table test. Other clinical parameters such as RBD, Unified Parkinson's Disease Rating Scale (UPDRS), cognition, Cross-Cultural Smell Identification Test (CCSIT), white matter hyperintensity (WMH), cardiac metaiodobenzylguanidine (MIBG) and striatal dopamine transporter (DAT) uptake were assessed. Plasma NFL levels were measured using Simoa platform. During mean 24.8 months of follow-up, 70 patients remained PD, 5 patients converted to Parkinson-plus syndrome (P + converter), and 2 were lost to follow-up. NFL level did not differ between PD and control groups (age-adjusted means 10.40 pg/mL vs 9.51 pg/mL, p = 0.151), but PD patients with OH (median 15.31 pg/mL) had higher levels compared with those without OH (median 9.2 pg/mL, p = 0.008), as well as the control group (median 9.7 pg/mL, p = 0.002). P + converter group had the highest plasma NFL level (38.17 pg/mL, p < 0.001). In a multiple regression analysis, OH, age, and disease duration independently correlated with plasma NFL level. This finding adds biomarker-based evidence for poor clinical outcomes associated with OH in patients with PD.

Ataxia Associated with CADASIL: a Pathology-Confirmed Case Report and Literature Review.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is primarily characterized by migraine, stroke, mood disturbances, and cognitive decline. Ataxia has seldom been reported as a presenting symptom. Here, we review reports of CADASIL presenting as ataxia and compare these to the first pathologically confirmed case of CADASIL presenting with progressive ataxia. A 50-year-old woman presented with progressive truncal ataxia. Brain magnetic resonance imaging (MRI) revealed white matter hyperintensities in the bilateral anterior temporal lobes, external capsules, and periventricular areas, but not the cerebellum. Electron microscopy of skin biopsy material revealed multiple granular osmiophilic materials. Genetic testing confirmed a c.4552C > A mutation in exon 25 of the NOTCH3 gene. CADASIL is a rare cause of progressive ataxia, and only four cases of CADASIL presenting with ataxia have been reported in the literature. We also discuss the possible pathophysiology of cerebellar ataxia associated with CADASIL.

Subthalamic deep brain stimulation improves vascular endothelial function in Parkinson's disease.

OBJECTIVES: Vascular health (white matter change, vascular risk factor, angiogenesis, microvascular alteration) is associated with clinical progression or levodopa-induced dyskinesia in PD. Vascular endothelial function is known to reflect the earliest vascular change. While DBS can improve motor and non-motor symptoms, the effect of DBS on vascular endothelial function is unknown. Thus, we aimed to investigate whether DBS surgery could impact vascular endothelial function in PD. METHOD: A total of 20 PD patients were recruited. Vascular endothelial function was evaluated with flow-mediated dilation (FMD). FMD was investigated before and after one year of DBS surgery. RESULTS: FMD improved (6.01 ± 1.58 to 6.84 ± 1.57, p = 0.027). While the level of homocysteine slightly decreased (13.8 ± 4.1 to 13.0 ± 3.2, p = 0.05), there was no significant correlation between FMD changes and homocysteine levels (r = 0.42, p = 0.065). FMD change was associated with baseline age (r = -0.59, p = 0.006) but not with disease duration (p = 0.73), baseline UPDRS III (p = 0.81), change of UPDRS III and dyskinesia, and LEDD change (p = 0.94). Multivariate linear regression analysis revealed that only age (B = -0.139; p = 0.024) was significantly and inversely correlated with the change of FMD. CONCLUSIONS: We found that STN-DBS improves vascular endothelial function in PD. Further studies are needed to clarify the exact pathogenesis and clinical implication of beneficial effects on vascular endothelial dysfunction in PD.

The effect of levodopa treatment on vascular endothelial function in Parkinson's disease.

OBJECTIVE: There has been increasing awareness that micro-vascular alteration or vascular inflammation has been associated with levodopa-induced dyskinesia in PD. Vascular endothelial function assessed by flow mediated dilation (FMD) is known to reflect early microvascular change. We compare the impact of levodopa or dopamine agonist treatment on the change of FMD in de novo PD patients. METHODS: This retrospective study used a selected sample from registry. We identified de-novo PD patients who underwent FMD at baseline, and follow-up FMD after 1 year (± 2 month) of levodopa (n = 18) or dopamine agonist (n = 18) treatment. RESULTS: FMD decreased after levodopa (8.60 ± 0.46 to 7.21 ± 0.4, p = 0.002) but there were no significant changes after DA treatment (8.33 ± 0.38 to 8.22 ± 0.33, p = 0.26). Homocysteine rose (11.52 ± 0.45 to 14.33 ± 0.68, p < 0.05) during levodopa treatment, but dopamine agonist had no effect (10.59 ± 0.38 to 11.38 ± 0.67, p = 0.184). Correlation analysis revealed that the changes in homocysteine level had non-significant correlation with FMD change (r = - 0.30, p = 0.06). FMD change was not associated with age (p = 0.47), disease duration (p = 0.81), baseline motor UPDRS (p = 0.43), motor UPDRS change (p = 0.64), levodopa equivalent dose change (p = 0.65). CONCLUSIONS: We found that 1-year levodopa treatment may adversely affect vascular endothelial function in de novo PD. Further studies are needed to clarify the exact pathogenesis and clinical implication of levodopa-induced endothelial dysfunction in PD.

Striatal Hyperperfusion Observed in Dual-Phase 18F-FP-CIT PET Imaging of Hyperglycemic Chorea.

ABSTRACT: A 76-year-old woman with a history of diabetes mellitus presented with right-side dominant generalized chorea. At presentation, her blood glucose level was 500 mg/dL with an HbA1C of 11%. Because the patient had been on levodopa treatment from her primary physician, a dual-phase 18F-FP-CIT PET scan was performed. The early-phase images showed increased perfusion in the bilateral striatum, and the delayed-phase images revealed decreased uptake in the left caudate. Hyperperfusion in the striatum may indicate the acute phase of hyperglycemic chorea. This image illustrates the advantage of adding early-phase scans in 18F-FP-CIT PET in differentiating various hyperkinetic and hypokinetic disorders.

Neurofilament light chain and cardiac MIBG uptake as predictors for phenoconversion in isolated REM sleep behavior disorder.

BACKGROUND: Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) is considered as a prodromal stage of either multiple system atrophy (MSA) or Lewy body disease (LBD; Parkinson's disease and dementia with Lewy bodies). However, current knowledge is limited in predicting and differentiating the type of future phenoconversion in iRBD patients. We investigated the role of plasma neurofilament light chain (NfL) and cardiac metaiodobenzylguanidine (MIBG) uptake as predictors for phenoconversion. METHODS: Forty patients with iRBD were enrolled between April 2018 and October 2019 and prospectively followed every 3 months to determine phenoconversion to either MSA or LBD. Plasma NfL levels were measured at enrollment. Cardiac MIBG uptake and striatal dopamine transporter uptake were assessed at baseline. RESULTS: Patients were followed for a median of 2.92 years. Four patients converted to MSA and 7 to LBD. Plasma NfL level at baseline was significantly higher in future MSA-converters (median 23.2 pg/mL) when compared with the rest of the samples (median 14.1 pg/mL, p = 0.003). NfL level above 21.3 pg/mL predicted phenoconversion to MSA with the sensitivity of 100% and specificity of 94.3%. Baseline MIBG heart-to-mediastinum ratio of LBD-converters (median 1.10) was significantly lower when compared with the rest (median 2.00, p < 0.001). Heart-to-mediastinum ratio below 1.545 predicted phenoconversion to LBD with the sensitivity of 100% and specificity of 92.9%. CONCLUSIONS: Plasma NfL and cardiac MIBG uptake may be useful biomarkers in predicting phenoconversion of iRBD. Elevated plasma NfL levels may suggest imminent phenoconversion to MSA, whereas low cardiac MIBG uptake suggests phenoconversion to LBD.

Association of plasma α-synuclein with cardiac 123I-MIBG scintigraphy in early Parkinson's disease.

Cardiac 123I-metaiodobenzylguanidine (MIBG) uptake correlates with the extent of cardiac sympathetic denervation found in disease with Lewy pathology, such as Parkinson's disease (PD). Protein α-synuclein, the main component of Lewy body, is a candidate biomarker of PD, but its relationship with cardiac MIBG uptake has never been explored. Plasma α-synuclein levels were measured in 37 patients with early PD. Cardiac 123I-MIBG scintigraphy and 18F-FP-CIT brain PET were performed, and striatal dopamine transporter (DAT) uptake was quantified using automated segmentation. The relationships of plasma α-synuclein levels with cardiac MIBG and striatal DAT uptake were investigated. The plasma α-synuclein level correlated with early (R = 0.38, P = 0.033) and delayed (R = 0.49, P = 0.0055) MIBG heart-to-mediastinum (H/M) ratios, and its correlation with delayed H/M ratio remained significant after adjustment with age, disease duration, motor severity, and striatal DAT uptake (P = 0.016). The regional SUVRs of any subregions of caudate and putamen did not correlate with plasma α-synuclein level. In the patients with early PD, the plasma α-synuclein level correlated with cardiac sympathetic denervation, but not with nigrostriatal degeneration. This may suggest that plasma α-synuclein levels more readily reflect the peripheral deposition of Lewy bodies than their central deposition.

Factors associated with motor severity in vascular parkinsonism with normal dopamine transporter imaging.

INTRODUCTION: To delineate the determinants of motor severity in vascular parkinsonism (VaP), we investigated the impact of regional white matter intensity (WMH) burden and co-morbidities on the motor score in the patients with VaP and normal dopamine transporter (DAT) imaging. METHODS: In this multicenter, retrospective study, we reviewed the records of 63 patients diagnosed with VaP and normal DAT imaging on 18F-FP-CIT PET. Signal hyperintensities in deep white matter (DWMH), periventricular (PVH), basal ganglia (BG) regions, and infratentorial foci (ITF) were rated according to Scheltens scale, a semi-quantitative visual rating system. Motor severity was assessed with Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Regional hyperintensity scores, patients' demographics, and co-morbidities such as type 2 diabetes, hypertension, dyslipidemia, and previous stroke history were used as starting variables, and stepwise regression analysis was performed to select independent predictors of motor severity. RESULTS: PVH (R = 0.33, p = 0.008) and DWMH score (R = 0.31, p = 0.015) correlated with the motor severity, while BG and ITF scores did not. Diabetic patients had significantly higher motor scores compared with non-diabetics (34.7 (13.0) vs. 27.5 (12.4), p = 0.008). Other factors such as sex, BMI, hypertension, dyslipidemia, and previous history of stroke did not impact motor severity. In multivariate analysis, PVH scores and diabetes significantly correlated with motor severity. CONCLUSION: PVH burden and diabetes were independent factors associated with motor severity in VaP with normal DAT imaging. Our results suggest that diabetes, along with white matter hyperintensities, may have a significant role in the development of motor symptoms in VaP.

Serial 18F-FP-CIT and FDG PET in Fulminant Corticobasal Syndrome.

ABSTRACT: Corticobasal syndrome (CBS) is characterized by a slow progressive cognitive decline, apraxia, myoclonus, dystonia, and parkinsonism. We experienced a rapidly progressing CBS patient (onset to bed-ridden within 2 years) presenting only with resting tremor but showing complete unilateral loss of dopamine transporter binding. This case exhibited distinct FDG PET findings involving the unilateral severe anterior frontal cortex, caudate nucleus, and contralateral cerebellum, which is different from classical CBS. However, to date, no detailed serial functional imaging study has been performed in rapidly progressing CBS, so these FDG PET and CIT PET findings may help clinicians to recognize this fulminant type of corticobasal degeneration.

Is an Isolated Weight-Holding Tremor a New Subtype of Isometric Tremor?

A weight-holding tremor is a rare type of hand tremor that occurs only when someone holds some weight. Here we report three cases of isolated weight-holding tremors, of which one patient was diagnosed with Parkinson's disease (PD) and the others as a variant of essential tremor (ET). A 68-year-old woman presented with a left-hand tremor that appeared only when she held objects with some weight. Her tremor was reminiscent of the re-emergent tremor of PD, and dopamine transporter imaging revealed reduced uptake at the right posterior putamen. A 21-year-old man and a 71-year-old woman also presented with similar weight-holding tremors. However, these tremors were not re-emergent, and no signs of parkinsonism were observed during follow-up. Although the underlying etiologies of these tremors differed, all three tremors worsened as the held weight increased. These tremors could be isolated isometric tremors, but further research is needed to clarify the nature of this rare tremor.