Health-related quality of life of adults with spinal muscular atrophy: insights from a nationwide patient registry in Germany.

PURPOSE: Spinal muscular atrophy (SMA) is a rare, autosomal-recessive disease characterized by progressive muscular atrophy and weakness resulting in substantial disability and short life expectancy. The objective of this cross-sectional study was to assess health-related quality of life (HRQoL) of adults with SMA in Germany in the era of disease-modifying therapy. METHODS: Adults with SMA were recruited via the German national TREAT-NMD SMA patient registry. HRQoL was measured using the EQ-5D-5L, the Health Utilities Index Mark III (HUI), and the Short Form (36) Health Survey (SF-36). Estimates were stratified by current best motor function of the lower limb and trunk (i.e., non-sitter, sitter, and walker) and SMA type (i.e., type I, II, and III). RESULTS: A total of 82 adults with SMA (mean age: 42 years, 51% female) self-completed the study questionnaire. The mean EQ-5D-5L utility was estimated at 0.5135 (range across subgroups: 0.31-0.99), mean EQ-VAS at 69.71 (64.67-90.00), mean HUI-derived utility at 0.3171 ( - 0.02-0.96), mean SF-6D utility at 0.6308 (0.58-0.65), and mean SF-36 Physical Component Summary and Mental Health Component Summary scores at 33.78 (9.92-53.10) and 53.49 (21.02-72.25), respectively. CONCLUSIONS: We show that adults with SMA experience considerable impairment across a wide range of health dimensions, including mobility, dexterity, pain, and emotional well-being. However, our results exhibit non-trivial variability across clinical subgroups and HRQoL measures. These data contribute to our understanding of the subjective impact of living with a severely debilitating neuromuscular disease, such as SMA.

Self-Reported Health-Related Quality of Life of Children with Spinal Muscular Atrophy: Preliminary Insights from a Nationwide Patient Registry in Germany.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare, severely debilitating neuromuscular disease characterized by a wide spectrum of progressive muscular atrophy and weakness. OBJECTIVES: The objective of this pilot study was to estimate self-assessed health-related quality of life (HRQoL) of children with SMA. METHODS: Children with SMA were recruited via the German national TREAT-NMD SMA patient registry and asked to self-complete the following rating-scales: KIDSCREEN-27, KINDL, the PedsQL 3.0 Neuromuscular Module (PedsQL 3.0 NMM), EQ-5D-5L, and the Health Utilities Index (HUI). Estimates were stratified by current best motor function of the lower limb and trunk (i.e., non-sitter, sitter, and walker) and SMA type (i.e., type I, II, and III). RESULTS: In total, 17 children with SMA (mean age: 9.88 years, SD: 4.33 years, range: 5-16 years; 59% female) participated in the study. Across examined strata, the mean KIDSCREEN-27 total score was estimated at between 48.24 and 83.81; the mean KINDL total score at between 60.42 and 76.73; the mean PedsQL 3.0 NMM total score at between 58.00 and 83.83; the mean EQ-5D-5L utility at between 0.31 and 0.99; and the mean HUI-derived utility at between -0.02 and 0.96. CONCLUSIONS: The results from this pilot study show that German children with SMA, despite significant physical disability, have surprisingly good HRQoL as assessed using KIDSCREEN-27. Yet, many reside in health states associated with low utility. The disease burden was generally higher among non-sitters compared with walkers, and SMA type I compared with type III, but more research is needed to further delineate this variability. Our preliminary findings contribute to the understanding of HRQoL in pediatric patients with SMA and should be helpful to inform the design of future studies of this patient population.

Alterations in pathogen-specific cellular and humoral immunity associated with acute peripheral facial palsy of infectious origin.

BACKGROUND: Peripheral facial palsy (PFP) is a common neurologic symptom which can be triggered by pathogens, autoimmunity, trauma, tumors, cholesteatoma or further local conditions disturbing the peripheral section of the nerve. In general, its cause is often difficult to identify, remaining unknown in over two thirds of cases. As we have previously shown that the quantity and quality of pathogen-specific T cells change during active infections, we hypothesized that such changes may also help to identify the causative pathogen in PFPs of unknown origin. METHODS: In this observational study, pathogen-specific T cells were quantified in blood samples of 55 patients with PFP and 23 healthy controls after stimulation with antigens from varicella-zoster virus (VZV), herpes-simplex viruses (HSV) or borrelia. T cells were further characterized by expression of the inhibitory surface molecule CTLA-4, as well as markers for differentiation (CD27) and proliferation (Ki67). Pathogen-specific antibody responses were analyzed using ELISA. Results were compared with conventional diagnostics. RESULTS: Patients with PFP were more often HSV-seropositive than controls (p = 0.0003), whereas VZV- and borrelia-specific antibodies did not differ between groups. Although the quantity and general phenotypical characteristics of antigen-specific T cells did not differ either, expression of CTLA-4 and Ki67 was highly increased in VZV-specific T cells of 9 PFP patients, of which 5 showed typical signs of cutaneous zoster. In the remaining 4 patients, a causal relationship with VZV was possible but remained unclear by clinical standard diagnostics. A similar CTLA-4- and Ki67-expression profile of borrelia-specific T cells was also found in a patient with acute neuroborreliosis. DISCUSSION: In conclusion, the high prevalence of HSV-seropositivity among PFP-patients may indicate an underestimation of HSV-involvement in PFP, even though HSV-specific T cell characteristics seem insufficient to identify HSV as a causative agent. In contrast, striking alterations in VZV- and borrelia-specific T cell phenotype and function may allow identification of VZV- and borrelia-triggered PFPs. If confirmed in larger studies, antigen-specific immune-phenotyping may have the potential to improve specificity of the clinical diagnosis.

Striatal dopamine transporters and cognitive function in Parkinson's disease.

BACKGROUND: Idiopathic Parkinson's disease (PD) is characterized by clinical motor symptoms including hypokinesia, rigidity and tremor. In addition to the movement disorder, cognitive deficits are commonly described. In the present study, we applied FP-CIT SPECT to investigate the impact of nigrostriatal dopaminergic degeneration on cognitive function in PD patients. METHODS: Fifty-four PD patients underwent [123I]FP-CIT SPECT and CERAD (Consortium to Establish a Registry for Alzheimer's Disease) testing. FP-CIT SPECT visualized the density of presynaptic dopamine transporters in both striata, each subdivided into a limbic, executive and sensorimotor subregion according to the atlas of Tziortzi et al (Cereb Cortex 24, 2014, 1165). CERAD testing quantified cognitive function. RESULTS: In the CERAD testing, PD patients exhibited deficits in the domains of semantic memory, attention, visuospatial function, non-verbal memory and executive function. After correction for multiple testing, the performance of the subtests Figure Recall and Trail-Making Test A correlated significantly with FP-CIT uptake into the ipsilateral executive subregion. The performance of the subtest Figure Saving correlated significantly with FP-CIT uptake into the contralateral executive subregion. CONCLUSIONS: The significant correlation between cognitive function and density of nigrostriatal dopamine transporters, as assessed by FP-CIT SPECT, indicate that striatal dopaminergic pathways-primarily the executive striatal subregion-are relevant to cognitive processing in PD.

Gastric Motility in Parkinson's Disease is Altered Depending on the Digestive Phase and Does Not Correlate with Patient-Reported Motor Fluctuations.

BACKGROUND: Altered gastric motility is a frequent non-motor symptom of Parkinson's disease (PD). It has been hypothesized that disturbed gastric motility contributes to motor fluctuations in PD due to an erratic gastro-duodenal transport and an unpredictable absorption of drugs. OBJECTIVE: We investigated whether patient-reported fluctuations are associated with parameters of gastric motility visualized by real-time magnetic resonance imaging (MRI) of the stomach. METHODS: We analyzed real-time MRI-scans of the stomach after an overnight fasting period in 16 PD patients and 20 controls. MRI was performed 1) in the fasting state, 2) directly after a test meal, and 3) 4 hours postprandially. Gastric motility indices were calculated and compared between groups. RESULTS: MRI showed an attenuated gastric motility in PD patients compared to controls. The difference was most obvious in the early postprandial phase. Gastric motility was not associated with patient-reported motor fluctuations. Using an iron-containing capsule we were able to retrace retention of drugs in the stomach. CONCLUSION: The results of this study stress the importance of considering the phase of digestion when investigating gastric motility in PD. Despite theoretical considerations, we did not find robust evidence for an association between MRI parameters of gastric motility and patient-reported motor fluctuations. For future studies that aim to investigate gastric motility in PD by MRI, we suggest multiple short-time MRIs to better track the whole gastro-duodenal phase in PD. Such an approach would also allow to retrace the retention of drugs in the stomach as shown by our approach using an iron-containing capsule.

Corrigendum: Off-Label Use of Ataluren in Four Non-ambulatory Patients With Duchenne Muscular Dystrophy: Effects on Cardiac and Pulmonary Function and Muscle Strength.

[This corrects the article DOI: 10.3389/fped.2018.00316.].

Third ventricular width assessed by transcranial ultrasound correlates with cognitive performance in Parkinson's disease.

INTRODUCTION: Cognitive impairment and dementia are common in PD; however, no stable marker of cognitive dysfunction is available. Transcranial sonography can evaluate global and focal brain atrophy and has been widely used in the differential diagnosis of parkinsonism. METHODS: 225 consecutive PD patients were recruited in a two-center cross sectional study and underwent a standardized sonographic protocol assessing the third ventricle's width and substantia nigra hyperechogenicity. All subjects were evaluated with an extensive motor and cognitive battery. RESULTS: 222 PD patients were included and classified as PD with normal cognition (PDNC; n = 130), mild cognitive impairment (PD-MCI; n = 61) and dementia (PDD; n = 31). Ventricular width correlated strongly with cognitive performance in all cognitive domains (p < 0.001) while SN size did not. PDD patients had significantly wider ventricles than PD patients without dementia (p < 0.001) while differences between PD-MCI and PDNC or PDD were less strong (p < 0.05). There were no group differences in SN size. ROC analyses resulted in age-related cut-offs of third ventricular diameter for the prediction of PDD (6.0 and 7.5 mm for subjects < and ≥70 years of age, respectively). These cut-offs significantly differentiated PDD from PDNC (p < 0.001) and from all patients without dementia (PDNC + PD-MCI; p < 0.001). CONCLUSIONS: The third ventricular diameter correlated with cognitive performance in all domains and was able to differentiate PDD patients from those without dementia. Longitudinal studies are warranted to evaluate whether transcranial sonography could identify PD patients at risk for a rapid cognitive decline.

Off-Label Use of Ataluren in Four Non-ambulatory Patients With Nonsense Mutation Duchenne Muscular Dystrophy: Effects on Cardiac and Pulmonary Function and Muscle Strength.

About 15% of Duchenne muscular dystrophy (DMD) cases are caused by point mutations leading to premature stop codons and disrupted synthesis of the dystrophin protein. Stop codon read-through therapy is available with the drug Ataluren (Translarna® by PTC Therapeutics). Following positive results in ambulatory nmDMD (non-sense mutation Duchenne muscular dystrophy) patients, Ataluren received conditional approval in ambulant nmDMD patients by the EMA in 2014. However, there are limited data on non-ambulatory nmDMD patients treated with Ataluren. Here, we report our experience in four non-ambulatory nmDMD patients. Routine investigations included cardiac function, pulmonary function tests and muscle strength. We compared changes in left ventricular fractional shorting, forced volume vital capacity and BMI from two defined time periods (18-26-month period prior to and after Ataluren start). Mean age at loss of ambulation was 10.1 ± 0.5 years, mean age when initiating Ataluren treatment 14.1 ± 1.4 years. Serial echocardiography, pulmonary lung function tests, and assessment of muscle strength indicated mild attenuation of disease progression after initiation of Ataluren treatment. A possible side effect of Ataluren was a reduction in BMI. There were no adverse clinical effects or relevant abnormalities in routine laboratory values. We conclude that Ataluren appears to mildly ameliorate the clinical course in our patients with a good safety profile. However, larger clinical trials are required to assess the role of Ataluren and its long-term impact on disease progression in non-ambulant nmDMD patients.

MIBG scintigraphy of the major salivary glands in multiple system atrophy.

We applied MIBG scintigraphy to measure the sympathetic innervation of the major salivary glands in 28 patients with multiple system atrophy (MSA) and 15 controls. MIBG uptake did not differ significantly between MSA patients and controls. This normal MIBG uptake correlates with predominantly intact postganglionic sympathetic innervation in MSA.

Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinson's disease.

BACKGROUND/OBJECTIVE: Intestinal inflammation and increased intestinal permeability (both possibly fueled by dysbiosis) have been suggested to be implicated in the multifactorial pathogenesis of Parkinson's disease (PD). The objective of the current study was to investigate whether fecal markers of inflammation and impaired intestinal barrier function corroborate this pathogenic aspect of PD. METHODS: In a case-control study, we quantitatively analyzed established fecal markers of intestinal inflammation (calprotectin and lactoferrin) and fecal markers of intestinal permeability (alpha-1-antitrypsin and zonulin) in PD patients (n = 34) and controls (n = 28, group-matched for age) by enzyme-linked immunosorbent assay. The study design controlled for potential confounding factors. RESULTS: Calprotectin, a fecal marker of intestinal inflammation, and two fecal markers of increased intestinal permeability (alpha-1-antitrypsin and zonulin) were significantly elevated in PD patients compared to age-matched controls. Lactoferrin, as a second fecal marker of intestinal inflammation, showed a non-significant trend towards elevated concentrations in PD patients. None of the four fecal markers correlated with disease severity, PD subtype, dopaminergic therapy, or presence of constipation. CONCLUSIONS: Fecal markers reflecting intestinal inflammation and increased intestinal permeability have been primarily investigated in inflammatory bowel disease so far. Our data indicate that calprotectin, alpha-1-antitrypsin and zonulin could be useful non-invasive markers in PD as well. Even though these markers are not disease-specific, they corroborate the hypothesis of an intestinal inflammation as contributing factor in the pathogenesis of PD. Further investigations are needed to determine whether calprotectin, alpha-1-antitrypsin and zonulin can be used to define PD subgroups and to monitor the effect of interventions in PD.

Reduced MIBG accumulation of the parotid and submandibular glands in idiopathic Parkinson's disease.

INTRODUCTION: Alpha-synuclein pathology (ASP) is a characteristic histopathological finding in idiopathic Parkinson's disease (PD). The ASP involves not only the brain but also extracranial structures. In the present study we utilized MIBG scintigraphy to measure the sympathetic innervation of the major salivary glands. We were interested in whether MIBG uptake in the major salivary glands represents a potential biomarker for ASP in PD. METHODS: We investigated 77 PD patients (age 61 ± 10 years, mean ± SD), while 15 non-PD patients (age 58 ± 15 years) with arterial hypertension, who underwent MIBG scintigraphy to exclude pheochromocytoma, served as age-matched controls. The MIBG uptake of the parotid glands and the submandibular glands was quantified by means of a region of interest technique. The sublingual glands were too small for an exact measurement. We applied Generalized Estimating Equations (GEE) to identify and remove factors which may bias the statistical correlation analysis. RESULTS: The PD patients showed a significantly lower MIBG uptake in the parotid and submandibular glands than the controls (p < 0.0001). MIBG uptake in the PD patients did not correlate with clinical severity (Hoehn and Yahr stage, motor part of the UPDRS) or disease duration. CONCLUSION: MIBG uptake in the parotid and submandibular glands might be a candidate biomarker for PD. The missing correlation between MIBG uptake and clinical PD parameters suggests that ASP of the extracranial sympathetic superior cervical ganglion, which innervates the major salivary glands, develops independently from the cerebral dopaminergic nigrostriatal ASP.

Comparison of IPX066 with carbidopa-levodopa plus entacapone in advanced PD patients.

BACKGROUND: IPX066, an investigational extended-release carbidopa-levodopa (CD-LD) preparation, has demonstrated a rapid attainment and prolonged maintenance of therapeutic LD plasma concentrations in advanced Parkinson's disease (PD). This phase-3 crossover study assessed its efficacy and safety vs. CD-LD plus entacapone (CL + E). METHODS: At baseline, all patients had motor fluctuations despite a stable regimen of CL + E or CD-LD-entacapone combination tablets (CLE). The study included a 6-week conversion from CL + E or CLE to IPX066, followed by two 2-week, double-blind crossover treatment periods in randomized order, one on IPX066 (and placebo CL + E), the other on CL + E (and placebo IPX066), separated by 1-week open-label IPX066 treatment. The primary efficacy measure was mean percent daily "off" time during waking hours (from patient diaries). RESULTS: Of 91 randomized patients, 84 completed the study. Their median daily LD dosage was 1495 mg from IPX066 and 600 mg from CL + E, corresponding, after correction for bioavailability, to an approximately 22% higher LD exposure on IPX066. Compared with CL + E, IPX066 demonstrated a lower percent "off" time (24.0% vs. 32.5%; p < 0.0001), lower "off" time (3.8 vs. 5.2 h/day; p < 0.0001), and higher "on" time without troublesome dyskinesia (11.4 vs. 10.0 h/day; p < 0.0001). Other endpoints, including patient-reported treatment preference, also favored IPX066 (p < 0.05). During double-blind treatment, 20.2% and 13.6% of patients reported adverse events on IPX066 and CL + E, respectively. The most common were dyskinesia (4 patients), insomnia (3), and confusional state (3) for IPX066, and fall (2) for CL + E. CONCLUSIONS: In advanced PD, IPX066 showed improved efficacy, compared with CL + E, and appeared to be well tolerated.

Nicotinic acetylcholine receptor density in cognitively intact subjects at an early stage of Parkinson's disease.

We investigated in vivo brain nicotinic acetylcholine receptor (nAChR) distribution in cognitively intact subjects with Parkinson's disease (PD) at an early stage of the disease. Fourteen patients and 13 healthy subjects were imaged with single photon emission computed tomography and the radiotracer 5-[(123)I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([(123)I]5IA). Patients were selected according to several criteria, including short duration of motor signs (<7 years) and normal scores at an extensive neuropsychological evaluation. In PD patients, nAChR density was significantly higher in the putamen, the insular cortex and the supplementary motor area and lower in the caudate nucleus, the orbitofrontal cortex, and the middle temporal gyrus. Disease duration positively correlated with nAChR density in the putamen ipsilateral (ρ = 0.56, p < 0.05) but not contralateral (ρ = 0.49, p = 0.07) to the clinically most affected hemibody. We observed, for the first time in vivo, higher nAChR density in brain regions of the motor and limbic basal ganglia circuits of subjects with PD. Our findings support the notion of an up-regulated cholinergic activity at the striatal and possibly cortical level in cognitively intact PD patients at an early stage of disease.

Performance of repetitive alternating elbow movements in Parkinson's disease.

BACKGROUND: Bradydiadochokinesia is one main clinical symptom in idiopathic Parkinson's disease (IPD). The pathogenesis of bradydiadochokinesia is not completely clear. METHODS: Fifteen patients with IPD and 15 age-matched healthy volunteers had to perform rhythmic alternating flexion and extension movements in the elbow joint. The rhythm was provided auditorily by a click tone stimulator. Six maneuvers (spatial extents of 48 and 83° at frequencies of 0.45, 0.75 and 1.25 Hz) had to be absolved. The potentiometer converted the horizontal forearm movements into a variable voltage. RESULTS: The duration of single movements varied more significantly in patients than in controls (p < 0.05; Mann-Whitney U test). Patients executed all conditions more slowly than controls, but this difference was only significant at the most difficult condition (83° at 1.25 Hz; p < 0.01). The movement amplitudes or their variability were not significantly different at any condition. No parameter correlated significantly with the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS) or with the duration of disease. CONCLUSION: An insufficient temporal coordination contributes to bradydiadochokinesia in IPD. This deficit occurs independently of other parkinsonian cardinal motor symptoms.

Is reduced myocardial sympathetic innervation associated with clinical symptoms of autonomic impairment in idiopathic Parkinson's disease?

Patients with idiopathic Parkinson's disease (IPD) have a reduced myocardial MIBG uptake in MIBG scintigraphy, indicating myocardial sympathetic denervation. We were interested whether this myocardial sympathetic denervation coincides with clinical symptoms of autonomic impairment in IPD patients. We performed MIBG scintigraphy, the SCOPA-AUT scale, a standardized medical history (developed in our clinic) and autonomic nervous system testing in 47 IPD patients (21 female, 26 male patients). We correlated myocardial MIBG uptake with the results of the SCOPA-AUT scale, the standardized medical history and the autonomic nervous system testing through the use of Spearman's correlation. Myocardial MIBG uptake correlated significantly (p < 0.05) with several items of the SCOPA-AUT scale (in female patients: perspiration during the night, in male patients: sum score, saliva dribbling of the mouth, difficulty swallowing, fainting, constipation), of the standardized medical history (in male patients: swollen ankles) and of the autonomic nervous system testing (all patients: sum score, Ewing orthostasis test). Remarkably, we found more significant correlations in male than in female patients. Reduced myocardial sympathetic innervation-as revealed by MIBG scintigraphy-is associated with clinical symptoms of autonomic impairment. This association is more pronounced in male than in female patients. The cause for this gender-specific phenomenon is unclear.

Principal Component Analysis of gait in Parkinson's disease: relevance of gait velocity.

Principal Component Analysis (PCA) is a method to estimate the relation between data points. We used PCA to analyse movements of the upper and lower extremities during treadmill walking in healthy subjects and two groups of Parkinsonian patients. Healthy subjects (n=35) showed a typical pattern with high values of PC1 and low values in a descending order of PC2-PC4. Increase of speed resulted in a significant increase of PC1 and a significant decrease of the following PC's. In more severely affected patients (n=19, UPDRS>20), PC1 was significantly decreased and PC2-PC4 were significantly increased compared to healthy subjects. Speed could be increased only within a small range without corresponding changes of the PC's. In less severely affected patients (n=17), significant differences of the PC's were only found with fast pace. Separate analysis of arms and legs revealed that these changes are only due to altered movements of the arm. Analysis of the pattern of PC's in response to changes of gait velocities reveal alterations even in less severely affected Parkinsonian patients. The changes of the PC's with higher gait velocities in healthy subjects are suggestive of an increase of intersegmental coordination. This is impaired even in less severely affected Parkinsonian patients.

Evaluation of transcranial sonographic findings and MIBG cardiac scintigraphy in the diagnosis of idiopathic Parkinson's disease.

The diagnosis of idiopathic Parkinson's disease (IPD) is based on clinical criteria. In the last two decades several neuroimaging methods using transcranial sonography (TCS) or radiolabelled tracers such as the myocardial MIBG scintigraphy were applied to support diagnosis of IPD. They have been used independently of each other and their interrelation is not yet clear. In the present study we analyzed the relation between findings of TCS, MIBG scintigraphy, and clinical presentation in 42 patients with IPD who were clinically diagnosed and underwent clinical follow-up over ≥3 years in order to confirm IPD diagnosis throughout the clinical course. The extent of substantia nigra hyperechogenicity (SN+) contralateral to the clinically more affected body side (SN(contra)) was compared to myocardial (123)I-MIBG uptake. SN(contra) did not correlate with the myocardial MIBG uptake (r = -0.10; p = 0.52). Both myocardial MIBG uptake and TCS did not correlate significantly with Hoehn and Yahr stage (r = -0.03; p = 0.87 and r = -0.10; p = 0.54, respectively). Sensitivity of TCS in the diagnosis of IPD was 79%, of MIBG scintigraphy 81%. The combination of both measurements reached a sensitivity of 95%. TCS and MIBG scintigraphy may disclose complementary aspects of IPD. The combined use of both neuroimaging methods might improve the diagnostic sensitivity regarding IPD.

Long-term course of substantia nigra hyperechogenicity in Parkinson's disease.

A hyperechogenicity of the (SN+) in transcranial sonography corroborates the diagnosis of idiopathic Parkinson's disease (iPD). Although it is thought to represent a biomarker of the disease that is independent of disease severity and progression, differing results have been reported describing a positive correlation of the size and advancing clinical stage. In 50 parkinsonian patients, transcranial ultrasound and clinical examination was performed twice with a mean time interval of 6.4 years. SN+ did not change in size significantly between the first and second examination, whereas clinical parkinsonian symptoms--as determined by the motor part of the UPDRS--significantly worsened (P < 0.001). We found a highly significant intraindividual correlation in SN+ sizes between both examinations (P < 0.001). The size of SN+ did not correlate with the UPDRS part III at the time of first or second ultrasound examination. Progression of motor symptoms between the first and second investigation did not correlate with the size of SN+ at baseline. Furthermore, even in the subgroup of patients with an interval of ≥ 8 years between examinations, there was no significant change in SN+ size. SN+ represents a largely stable biomarker in iPD and does not reflect disease progression. The size of SN+ does not predict the further course of the disease.