Transcranial sonography in patients with Parkinson's disease with glucocerebrosidase mutations

ObjectivesThe aim of this study was to search for possible differences in the findings of transcranial sonography (TCS) between groups of patients with glucocerebrosidase (GBA)-associated Parkinson's disease (PD) (4 patients with Gaucher disease type 1 and parkinsonism [GD+PD+] and 18 PD patients with heterozygous GBA mutations; [GBA+PD+]) and groups of 12 patients with Gaucher disease type 1 and no signs of parkinsonism (GD+PD?), 9 asymptomatic carriers of heterozygous GBA mutations (GBA+PD?), 32 sporadic PD patients (sPD), and 43 healthy controls.ResultsIn all groups of patients, except asymptomatic carriers of heterozygous GBA mutations (mean ± SD: 0.16 ± 0.03 cm²), the maximal areas of substantia nigra hyperechogenicity (aSN-max) was higher (GD+PD+: 0.28 ± 0.15 cm²; GD+PD?: 0.18 ± 0.06 cm²; GBA+PD+: 0.27 ± 0.06 cm²; sPD: 0.28 ± 0.10 cm²) when compared to controls (0.12 ± 0.08 cm²) (p = 0.001). In GBA-associated PD (GD+PD+ and GBA+PD+) and sPD, aSNmax values were very similar. Moderate or marked SN hyperechogenicity was present in 87.5% of sPD patients and in 83% of PD patients with heterozygous GBA mutations, but in only 11.6% of controls, and in 22.2% and 33.3% of patients from GBA+PD? and GD+PD? groups, respectively (p < 0.001). The prevalence of interrupted or missing echogenicity of the brainstem raphe differed between the groups (p = 0.046), while no difference was observed in the diameter of the third ventricle.ConclusionsTCS findings in GBA-associated PD were consistent to those of patients with sporadic PD.     

Comparison of motor fluctuations and l-dopa-induced dyskinesias in patients with familial and sporadic Parkinson''s disease

The aim of the present work was to study the characteristics of motor complications in a group of familial Parkinson's disease (fPD) patients in comparison with matched sporadic PD (sPD) patients. Fifty-one fPD and 51 sPD patients matched for age and disease duration, used as controls, were included in the study. The Unified Parkinson's Disease Rating Scale was completed during clinical examination and all patients were questioned about the characteristics of motor complications. The mean time from start of L-dopa therapy to the onset of motor fluctuations (MF) and L-dopa-induced dyskinesias (LID) as well as the mean time from symptom onset to the development of MF and LID was significantly shorter in the fPD group of patients. An analysis revealed a higher occurrence of MF and LID in fPD patients in the group with disease duration of 5 years or less. FPD may be associated with a higher prevalence and earlier onset of motor complications during the initial stages of the disease. Genetic factors may contribute to the specific characteristics of motor complications in fPD.     

Association of homozygous 7048G7049 variant in the intron six of Nurr1 gene with Parkinson's disease

OBJECTIVE: To determine whether the Nurr1 gene, which is critical for the development and maintenance of nigral dopaminergic neurons, is a risk factor associated with PD. BACKGROUND: The Nurrl gene is highly expressed in the dopaminergic neurons in the midbrain. Knockout of the gene results in agenesis of nigral dopaminergic neurons and heterozygous knockout mice increases 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. METHODS: This study included 105 patients with familial PD (fPD) and 120 patients with sporadic PD (sPD) and 221 age-matched healthy control subjects. The polymorphisms and mutations of the Nurr1 gene in patients with PD were initially examined by heteroduplex analysis and sequencing analysis from PCR-amplified Nurr1 gene fragments. A polymorphism in the BseRI restriction site was identified, and a relatively large-scale analysis then was conducted by three independent investigators who were blinded to the clinical status of the subjects. RESULTS: A homozygous 7048G7049 polymorphism was found in intron 6 of the Nurr1 gene, which was significantly higher in fPD (10/105; 9.5%) and in sPD (5/120; 4.2%) compared with healthy control subjects (2/221; 0.9%). The mean age and the SD at onset of these homozygote patients with PD was 52 +/- 15 years for fPD and 46 +/- 7 years for sPD. The clinical features of these homozygote patients with PD did not differ from those of typical PD. CONCLUSIONS: The homozygote polymorphism of 7048G7049 in intron 6 of the Nurr1 gene is associated with typical PD.     

Leukocyte glucocerebrosidase and β-hexosaminidase activity in sporadic and genetic Parkinson disease

BackgroundRecent reports have shown that the activities of lysosomal enzymes are altered in the CNS of sporadic PD (sPD) without GBA mutations. We hypothesized that the activities of lysosomal enzymes are altered in peripheral blood leukocytes (PBLs) of patients with sPD and other genetic parkinsonism.MethodsGlucocerebrosidase and β-hexosaminidase activities in PBLs were measured in 36 patients with sPD, 5 PD patients with PARK2 mutations, 10 patients with spinocerebellar ataxia (SCA) 17 with parkinsonism, and 20 healthy controls.ResultsThe glucocerebrosidase and β-hexosaminidase activities were not different in patients with sPD, PD with PARK2 mutations, and SCA17 with parkinsonism from those of the controls. In the patients with sPD, the activity of GCase was positively correlated with disease duration.ConclusionThe glucocerebrosidase and β-hexosaminidase activities in PBLs cannot be used as a biomarker in sPD and other genetic parkinsonism.     

Subthalamic and red nucleus volumes in patients with Parkinson’s disease: Do they change with disease progression?

ObjectiveTo examine a possible correlation between disease progression and the volumes of the subthalamic nucleus (STN) and red nucleus (RN) in patients with Parkinson disease (PD).MethodsTwelve patients with PD (mean time since diagnosis 10.8 ± 2.9 years) and age-matched 12 normal control subjects were enrolled. The volumes of the STN and RN were measured using 3-dimensional volume reconstructions of stereotactic magnetic resonance images.ResultsThe PD and control groups were similar with regard to age and gender. The STN volume was 0.13 ± 0.01 cm³ (mean ± SD) in PD patients and 0.27 ± 0.01 cm³ in controls (P < .001). The RN volume was 0.31 ± 0.02 cm³ in PD patients and 0.21 ± 0.02 cm³ in controls (P = .002). Positive correlations of RN volume with time since diagnosis (P = .004) and disease stage (P = .01) were observed. On average, the STN volumes were 48% smaller and RN volumes 32% larger in PD patients than in control subjects; the volumes of the two nuclei were negatively correlated (r = −0.46; P = .03).ConclusionsOur results suggest that advanced disease stage and longer disease duration are associated with increased RN volume. STN volume was significantly smaller in Parkinson group. These findings may be useful in estimating disease status and rate of progression, and may also have implications for surgical treatment. Larger studies are needed to validate these results and determine their usefulness.     

Eleven-Year Outcomes of Deep Brain Stimulation in Early-Stage Parkinson Disease

ObjectiveThe deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) pilot clinical trial randomized 30 patients (Hoehn & Yahr II off; medication duration 0.5–4 years; without dyskinesia/motor fluctuations) to optimal drug therapy (ODT) (early ODT) or bilateral subthalamic nucleus (STN) DBS plus ODT (early DBS+ODT). This study aims to report the 11-year outcomes of patients who completed the DBS in early-stage PD pilot clinical trial.Materials and MethodsAttempts were made to contact all 29 subjects who completed the two-year trial to participate in an 11-year follow-up study. Mixed-effects models compared overall trend in outcomes for randomization groups (fixed-effects: assigned treatment, year, their interaction; random-effect: subject) to account for repeated measures.ResultsTwelve subjects participated in this 11-year follow-up study (n = 8 early ODT, n = 4 early DBS+ODT). Participating subjects were 70.0 ± 4.8 years old with a PD medication duration of 13.7 ± 1.7 years (early DBS duration 11.5 ± 1.3 years, n = 4). Three early ODT subjects received STN-DBS as standard of care (DBS duration 6.5 ± 2.0 years). Early ODT subjects had worse motor complications (Unified Parkinson’s Disease Rating Scale [UPDRS]–IV) than early DBS+ODT subjects over the 11-year follow-up period (between-group difference = 3.5 points; p_interaction = 0.03). Early DBS+ODT was well-tolerated after 11 years and showed comparable outcomes to early ODT for other UPDRS domains, Parkinson Disease Questionnaire–39 (PDQ-39), and levodopa equivalent daily dose (LEDD).ConclusionsEleven years after randomization, early DBS+ODT subjects had fewer motor complications than early ODT subjects. These results should be interpreted with caution because only 40% of pilot trial subjects participated in this 11-year follow-up study. The Food and Drug Administration has approved the conduct of a pivotal clinical trial evaluating DBS in early-stage PD (IDEG050016).Clinical Trial RegistrationThe Clinicaltrials.gov registration number for the study is NCT00282152.     

Magnetic resonance imaging as a non-invasive tool to assess gastric emptying in mice

Background

Methods to study gastric emptying in rodents are time consuming or terminal, preventing repetitive assessment in the same animal. Magnetic resonance imaging (MRI) is a non-invasive technique increasingly used to investigate gastrointestinal function devoid of these shortcomings. Here, we evaluated MRI to measure gastric emptying in control animals and in two different models of gastroparesis.

Methods

Mice were scanned using a 9.4 Tesla MR scanner. Gastric volume was measured by delineating the stomach lumen area. Control mice were scanned every 30 min after ingestion of a 0.2 g meal and stomach volume was quantified. The ability of MRI to detect delayed gastric emptying was evaluated in models of morphine-induced gastroparesis and streptozotocin-induced diabetes.

Key Results

Magnetic resonance imaging reproducibly detected increased gastric volume following ingestion of a standard meal and progressively decreased with a half emptying time of 59 ± 5 min. Morphine significantly increased gastric volume measured at t = 120 min (saline: 20 ± 2 vs morphine: 34 ± 5 mm³; n = 8–10; p < 0.001) and increased half emptying time using the breath test (saline: 85 ± 22 vs morphine: 161 ± 46 min; n = 10; p < 0.001). In diabetic mice, gastric volume assessed by MRI at t = 60 min (control: 23 ± 2 mm³; n = 14 vs diabetic: 26 ± 5 mm³; n = 18; p = 0.014) but not at t = 120 min (control: 21 ± 3 mm³; n = 13 vs diabetic: 18 ± 5 mm³; n = 18; p = 0.115) was significantly increased compared to nondiabetic mice.

Conclusions and Inferences

Our data indicate that MRI is a reliable and reproducible tool to assess gastric emptying in mice and represents a useful technique to study gastroparesis in disease models or for evaluation of pharmacological compounds.     

Diabetes mellitus is independently associated with more severe cognitive impairment in Parkinson disease

BackgroundThere is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied.ObjectiveTo investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations.MethodsCross-sectional study. Patients with PD (n = 148); age 65.6 ± 7.4 years, Hoehn and Yahr stage 2.4 ± 0.6, with (n = 15) and without (n = 133) comorbid type II DM, underwent [¹¹C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [¹¹C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates.ResultsThere were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (−0.98 ± 1.01) compared to the non-diabetics (−0.36 ± 0.91; F = 7.78, P = 0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F = 8.39, P < 0.0001).ConclusionDiabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than disease-specific neurodegenerations.     

Tissue ghrelin level and gastric emptying rate in adult patients with celiac disease

Abstract Celiac disease (CD) patients show a number of gastrointestinal motor abnormalities. Ghrelin, a gastric peptide implicated in short‐term feeding control and long‐term body weight regulation, has been recently considered a key regulator of gastric motility. The aim of this study was to evaluate the gastric emptying rate of solids and the density of ghrelin‐immunopositive cells in adult CD patients before and at least 1 year after starting a gluten‐free diet. Twenty CD patients (M 8/F 12; mean age 36 years) and 10 controls underwent endoscopy with gastric and duodenal biopsies and ¹³C‐octanoic acid breath test to measure gastric emptying of solids. Celiac disease patients repeated the protocol at least 1 year after starting gluten‐free diet. Ghrelin tissue levels were evaluated by immunohistochemistry on gastric mucosa specimens. Gastric emptying time was normal in all control subjects (t_1/2 = 89 ± 16 min) while it was delayed in CD patients prior to gluten‐free diet (t_1/2 = 252 ± 101 min; P < 0.005). The mean number of ghrelin‐positive cells/field (×400) was 14.4 ± 2.7 in controls and 25.3 ± 5.7 in CD patients respectively (P < 0.0001). Gluten withdrawal was effective in normalizing gastric emptying time in all CD patients (97 ± 14 min; P < 0.0001) and resulted in a significant reduction of the density of ghrelin‐immunopositive cells (19.8 ± 5.4; P < 0.0001). The density of ghrelin‐positive cells correlated directly with the degree of duodenal damage (P < 0.001) and inversely with the body mass index of CD patients (P < 0.0001). However, in neither CD patients nor controls, a correlation between tissue ghrelin levels and gastric emptying rate was detected. In conclusion, tissue ghrelin level does not correlate with gastric emptying rate in adult CD patients and in controls.     

Diabetes is associated with postural instability and gait difficulty in Parkinson disease

BackgroundComorbid diabetes may be associated with more severe motor impairment in Parkinson disease. In normal elderly individuals, diabetes is associated with parkinsonian features, including gait difficulty and rigidity, though not tremor. Whether diabetes contributes to increased motor dysfunction in Parkinson disease by exacerbating nigrostriatal dopaminergic denervation or through intensification of extranigral pathology is unknown.MethodsWe performed a case–control study (n = 39) involving 13 Parkinson disease subjects (age 66.4yrs ± 5.5; duration of disease 6.9yrs ± 4.4) with diabetes and 26 age, gender, and duration-of-disease-matched Parkinson disease controls without diabetes. All subjects underwent [¹¹C]dihydrotetrabenazine vesicular monoamine transporter type-2 positron emission tomography imaging to assess striatal dihydrotetrabenazine distribution volume ratio and Unified Parkinson disease rating scale motor examination to determine rigidity, bradykinesia, tremor, and postural instability and gait difficulty subscores. Magnetic resonance imaging scans were analyzed to assess leukoaraiosis burden.ResultsAfter controlling for nigrostriatal dopaminergic denervation, Parkinson disease subjects with diabetes displayed greater postural instability and gait difficulty subscores (t = 3.81, p = 0.0005). There were no differences in bradykinesia, rigidity, or tremor subscores between cases and controls. The association between diabetes and postural instability and gait difficulty persisted after controlling for comorbid hypertension and body mass index. Leukoaraiosis, distal vibratory sense, and levodopa dose equivalents did not differ significantly between cases and controls.ConclusionsDiabetes may contribute to postural instability and gait difficulty in Parkinson disease through mechanisms other than nigrostriatal dopaminergic denervation.     

Validation of a new olfactory test for Chinese Parkinson’s disease patients

IntroductionHyposmia is a common non-motor symptom in Parkinson’s disease (PD) and has been used to assist PD diagnosis and early screening of prodromal patients. Although the Brief Smell Identification Test (B-SIT) is the most commonly used olfactory test, its utility was limited by the culture difference in recognition of the smells included in the test. We have developed a new modified B-SIT test for Chinese (B-SITC), and validated and compare it with B-SIT in Chinese PD patients.MethodsFrom 2015 to 2018, PD patients were recruited from the Movement Disorder Clinic of Xuanwu Hospital and healthy controls were recruited from the Beijing Longitudinal Study on Aging Cohort II. The two olfactory tests were used in healthy volunteers and PD patients.ResultsA total of 428 subjects participated in the study: 211 healthy controls and 217 PD patients. The average B-SIT and B-SITC scores were significantly different between control and PD groups (B-SIT, 9.18 ± 1.94 vs. 6.90 ± 2.44, P = 0.0001; B-SITC, 8.60 ± 1.93 vs. 5.91 ± 2.21, P = 0.0001). The B-SITC had good sensitivity (73.1%), specificity (76.8%), positive predictive value (76.8%), and negative predictive value (73.1%) for the diagnosis of Chinese PD, and the area under the curve (AUC) value was greater for the B-SITC than for the B-SIT (0.838 vs. 0.761).ConclusionsThe B-SITC is useful for the clinical assessment of olfactory function in Chinese PD patients.     

Risky driving and pedunculopontine nucleus-thalamic cholinergic denervation in Parkinson disease

BackgroundIt is unknown whether driving difficulty in Parkinson disease (PD) is attributable to nigrostriatal dopaminergic or extranigral non-dopaminergic neurodegeneration.ObjectiveTo investigate in vivo imaging differences in dopaminergic and cholinergic innervation between PD patients with and without a history of risky driving.MethodsThirty non-demented PD subjects (10 women/20 men) completed a driving survey. These subjects had previously undergone (+)-[¹¹C] dihydrotetrabenazine vesicular monoamine transporter 2 and [¹¹C] methyl-4-piperidinyl propionate acetylcholinesterase PET imaging. Acetylcholinesterase PET imaging assesses cholinergic terminal integrity with cortical uptake largely reflecting basal forebrain and thalamic uptake principally reflecting pedunculopontine nucleus integrity.ResultsEight of thirty subjects reported a history of risky driving (been pulled over, had a traffic citation, or been in an accident since PD onset) while 22 had no such history (safe drivers). There was no difference in striatal dihydrotetrabenazine vesicular monoamine transporter uptake between risky and safe drivers. There was significantly less thalamic acetylcholinesterase activity in the risky drivers compared to safe drivers (0.0513 ± 0.006 vs. 0.0570 ± 0.006, p = 0.022) but no difference in neocortical acetylcholinesterase activity. Using multivariable logistic regression, decreased thalamic acetylcholinesterase activity remained an independent predictor of risky driving in PD even after controlling for age and disease duration.ConclusionsRisky driving is related to pedunculopontine nucleus-thalamic but not neocortical cholinergic denervation or nigrostriatal dopaminergic denervation in PD. This suggests that degeneration of the pedunculopontine nucleus, a brainstem center responsible for postural and gait control, plays a role in the ability of PD patients to drive.     

Impaired contrast sensitivity is associated with more severe cognitive impairment in Parkinson disease

ObjectivesDopaminergic degeneration affects both nigrostriatal projection neurons and retinal amacrine cells in Parkinson disease (PD). Parkinsonian retinopathy is associated with impaired color discrimination and contrast sensitivity. Some prior studies described associations between color discrimination deficits and cognitive deficits in PD, suggesting that contrast discrimination deficits are due, at least in part, to cognitive deficits in PD. We investigated the relationship between cognitive deficits and impaired contrast sensitivity in PD.MethodsPD subjects, n = 43; 15F/28M; mean age 66.5 ± 8.2, Hoehn and Yahr stage 2.6 ± 0.6, and duration of disease of 6.2 ± 5.0 years underwent neuropsychological and Rabin contrast sensitivity testing.ResultsMean Rabin contrast sensitivity score was 1.34 ± 0.40. Bivariate analyses showed significant correlation between Rabin contrast sensitivity scores and global cognitive z-scores (R = 0.54, P = 0.0002). Cognitive domain Z-score post hoc analysis demonstrated most robust correlation between Rabin scores and executive functions (R = 0.49, P = 0.0009), followed by verbal learning (R = 0.44, P = 0.0028), visuospatial (R = 0.39, P = 0.001) and attention z-scores (R = 0.32, P = 0.036).ConclusionsImpaired contrast sensitivity in PD is robustly associated with cognitive deficits, particularly executive function deficits. These results suggest that contrast sensitivity may be a useful biomarker for cognitive changes in PD and may have implications for driving safety evaluations in PD.     

Is there a difference in gastric emptying between Parkinson’s disease patients under long-term <Emphasis Type="SmallCaps">l</Emphasis>-dopa therapy with and without motor fluctuations? An analysis using the <Superscript>13</Superscript>C-acetate breath test

The mechanism underlying the motor fluctuations that develop after long-term l-dopa therapy is not fully known. It has been speculated that malabsorption of l-dopa from the small intestine occurs. It was reported that gastric retention in Parkinson’s disease (PD) patients with motor fluctuations is increased as compared with that in PD without fluctuations. Because l-dopa therapy may worsen the symptoms of delayed gastric emptying (GE), it was not clear whether the delayed GE of PD patients with motor fluctuation was affected by l-dopa therapy. We assessed GE in PD patients with and without motor fluctuations. We investigated GE in 40 patients with PD under long-term l-dopa therapy, 20 fluctuators with “delayed-on” and “no-on” phenomena, 20 nonfluctuators, and 20 healthy volunteers. GE was examined by the ¹³C-acetate breath test (¹³C-ABT) [the half emptying time (HET), the peak time of the ¹³C-%-dose-excess curve (T _max)], with expirations collected for 4 h after a test meal and analyzed for ¹³CO₂ using an infrared (IR) spectrophotometer. The T _max of GE as assessed using the ¹³C-ABT was significantly delayed in all PD patients as compared with controls (P = 0.002). The HET was significantly delayed in all PD patients as compared with controls (P < 0.001). The T _max and HET were not significantly delayed in PD patients with motor fluctuations as compared with PD patients without motor fluctuations. These results demonstrated that GE is commonly delayed in PD patients with long-term l-dopa therapy. Delayed GE does not differ between PD patients with and without motor fluctuations. This finding demonstrated that the motor fluctuation in PD may not be influenced by GE.     

Transcranial sonography and functional imaging in glucocerebrosidase mutation Parkinson disease

BackgroundHeterozygous glucocerebrosidase (GBA) mutations are the leading genetic risk factor for Parkinson disease, yet imaging correlates, particularly transcranial sonography, have not been extensively described.MethodsTo determine whether GBA mutation heterozygotes with Parkinson disease demonstrate hyperechogenicity of the substantia nigra, transcranial sonography was performed in Ashkenazi Jewish Parkinson disease subjects, tested for the eight most common Gaucher disease mutations and the LRRK2 G2019S mutation, and in controls. [¹⁸F]-fluorodeoxyglucose or [¹⁸F]-fluorodopa positron emission tomography is also reported from a subset of Parkinson disease subjects with heterozygous GBA mutations.ResultsParkinson disease subjects with heterozygous GBA mutations (n = 23) had a greater median maximal area of substantia nigral echogenicity compared to controls (n = 34, aSNmax = 0.30 vs. 0.18, p = 0.007). There was no difference in median maximal area of nigral echogenicity between Parkinson disease groups defined by GBA and LRRK2 genotype: GBA heterozygotes; GBA homozygotes/compound heterozygotes (n = 4, aSNmax = 0.27); subjects without LRRK2 or GBA mutations (n = 32, aSNmax = 0.27); LRRK2 heterozygotes/homozygotes without GBA mutations (n = 27, aSNmax = 0.28); and GBA heterozygotes/LRRK2 heterozygotes (n = 4, aSNmax = 0.32, overall p = 0.63). In secondary analyses among Parkinson disease subjects with GBA mutations, maximal area of nigral echogenicity did not differ based on GBA mutation severity or mutation number. [¹⁸F]-fluorodeoxyglucose (n = 3) and [¹⁸F]-fluorodopa (n = 2) positron emission tomography in Parkinson disease subjects with heterozygous GBA mutations was consistent with findings in idiopathic Parkinson disease.ConclusionsBoth transcranial sonography and positron emission tomography are abnormal in GBA mutation associated Parkinson disease, similar to other Parkinson disease subjects.     

Cognitive impairment in carriers of glucocerebrosidase gene mutation in Parkinson disease patients

AimParkinson disease (PD) is the common neurodegenerative disease with motor and numerous non-motor symptoms, including cognitive impairment. Mutation of glucocerebrosidase (GBA) gene is the most common genetic risk factor of sporadic PD. The aim of this study was to assess clinical features of PD associated with GBA mutation.MethodsOne hundred and thirty-eight PD patients were involved and examined by the movement disorder specialist using several scales including Unified Parkinson Disease Rating Scale (UPDRS) part II and III, Hoehn and Yahr (H&Y) staging, Mini-Mental State Examination (MMSE) and Hamilton Depression Scale (HDS). The exons 8 and 9 of GBA was sequenced and screened for variants.ResultsThe GBA variants were found in 16 (11.6%) PD patients: N370S mutation in 5 (3.6%) and T369M variant in 11 (7.9%). No significant differences between the group of mutation carriers and non-carriers were found in relation to clinical features except for dementia (MMSE score < 26) occurring more often in N370S mutation carriers (60.0% vs 19.6%, p = 0.03).ConclusionThe N370S GBA mutation is the risk factor for cognitive impairment in PD patients.     

Treating sleep apnea in Parkinson's disease with C-PAP: feasibility concerns and effects on cognition and alertness

BackgroundObstructive sleep apnea (OSA) is highly prevalent in Parkinson disease (PD) and is known to contribute to cognitive impairment and daytime sleepiness. We investigated feasibility of continuous positive airway pressure treatment (CPAP) and its effects on subjective daytime sleepiness and cognitive profile in PD plus OSA subjects in a longitudinal three months follow up study.MethodsSeventy (age 71.7 ± 7.6, disease duration 9.9 ± 12.3, UPDRS-III 33.7 ± 12.5, MMSE 25.3 ± 3.6; years of education 7.7 ± 3.2) out of 228 consecutive PD patients undergoing in-lab video-polysomnography were found to have obstructive sleep apnea. Thirty-six subjects accepted to titrate therapeutic CPAP. Video-polysomnography, neuropsychological battery evaluating different cognitive domains and subjective scales for daytime sleepiness were scheduled at baseline and after three months. All the patients were given educational informations relative to diagnosis of OSA and benefits of OSA treatment, and an individualized training with CPAP.ResultsTwenty-seven (75%) subjects dropped out of the study due to CPAP intolerance. No demographic or disease-related variables (in particular, severity of OSA), could be found between subjects who completed the study versus those who dropped out. Nine subjects completed the three-month follow up, and there were no significant changes in subjective sleepiness, neuropsychological scores and sleep structure (except for reduction in apnea/hypopnea index and a trend toward increase in stage N3 sleep).ConclusionOur data show that feasibility of CPAP treatment can be significantly threatened by overall attrition rates. Further studies should consider well-structured adherence promoting interventions. The actual role of OSA as a determinant of the profile of subjective daytime sleepiness and cognition in PD, and the effects of CPAP in PD need to be further studied.     

Is there a delayed gastric emptying of patients with early-stage, untreated Parkinson's disease? An analysis using the 13C-acetate breath test

During the pre-symptomatic stage of Parkinson's disease (PD), the idiopathic PD related abnormal synuclein immunostaining is confined to the medulla oblongata and olfactory bulb, according to Braak. In the study of the enteric nervous system of PD, it has reported that Lewy bodies were found in the Auerbach's and Meissner's plexuses. These lesions may cause dysfunction of the gastrointestinal tract (GI) as pre-clinical symptoms of PD. However, because L: -dopa therapy itself may worsen the symptoms of the digestive tract function, it is needed to evaluate the gastrointestinal tract function in patients with early-stage, untreated (de novo) PD. In the present study, using the (13)C-acetate breath test ((13)C-ABT), we investigated gastric emptying in 20 untreated, early-stage PD patients and 40 treated, advanced-stage PD patients, and 20 healthy volunteers. Gastric emptying was examined by the (13)C-ABT [the half emptying time (HET), the peak time of the (13)C% dose-excess curve (T (max))]. The T (max) and HET of gastric emptying as assessed using the (13)C-ABT was significantly delayed in untreated, early-stage PD patients as compared to the controls (P < 0.001). The T (max) and HET of gastric emptying were not significantly delayed in untreated, early-stage PD patients as compared to treated, advanced-stage PD patients. The results demonstrated that delay in gastric emptying did not differ between untreated, early-stage and treated, advanced-stage PD patients. Gastric emptying of untreated, early-stage PD is already delayed. Delayed gastric emptying may be one of markers of the pre-clinical stage of PD.     

Increased muscle sympathetic nerve activity and impaired baroreflex control in isolated REM-sleep behavior disorder

ObjectiveChanges in baroreflex sensitivity have been reported in patients with idiopathic Parkinson’s disease (PD). We sought to investigate the hypothesis that patients with isolated rapid eye movement (REM)-sleep behavior disorder (iRBD), known to be a prodromal stage for PD, will show abnormalities in baroreflex control.MethodsTen iRBD patients were compared to 10 sex- and age-matched healthy controls. Their cardiovascular parameters and muscle sympathetic nerve activity (MSNA) were evaluated at rest and during baroreflex stimulation.ResultsMSNA at rest was higher in iRBD patients (burst frequency [BF]: 44 ± 3 bursts/min; burst incidence [BI]: 60 ± 8 bursts/100 heartbeats) as compared to the controls (BF: 29 ± 3 bursts/min, p < 0.001; BI: 43 ± 9 bursts/100 heartbeats, p < 0.001). During baroreflex stimulation, iRBD patients showed increased absolute values of MSNA (BF: F = 62.728; p < 0.001; BI: F = 16.277; p < 0.001) as compared to the controls. The iRBD patients had decreased diastolic blood pressure at baseline and during lower body negative pressure, but the level of significance was not met.ConclusionOur study shows increased MSNA and impaired baroreflex control in iRBD patients. We propose that the inhibitory effect of locus coeruleus on baroreflex function might be impaired, leading to the disinhibition of sympathetic outflow.SignificanceThese findings might reflect the destruction of brain areas due to the ascending P-α-synuclein deposits in iRBD patients.     

Delayed gastric emptying in Parkinson's disease

Gastrointestinal symptoms are evident in all stages of Parkinson's disease (PD). Most of the gastrointestinal abnormalities associated with PD are attributable to impaired motility. At the level of the stomach, this results in delayed gastric emptying. The etiology of delayed gastric emptying in PD is probably multifactorial but is at least partly related to Lewy pathology in the enteric nervous system and discrete brainstem nuclei. Delayed gastric emptying occurs in both early and advanced PD but is underdetected in routine clinical practice. Recognition of delayed gastric emptying is important because it can cause an array of upper gastrointestinal symptoms, but additionally it has important implications for the absorption and action of levodopa. Delayed gastric emptying contributes significantly to response fluctuations seen in people on long‐term l ‐dopa therapy. Neurohormonal aspects of the brain‐gut axis are pertinent to discussions regarding the pathophysiology of delayed gastric emptying in PD and are also hypothesized to contribute to the pathogenesis of PD itself. Ghrelin is a gastric‐derived hormone with potential as a therapeutic agent for delayed gastric emptying and also as a novel neuroprotective agent in PD. Recent findings relating to ghrelin in the context of PD and gastric emptying are considered. This article highlights the pathological abnormalities that may account for delayed gastric emptying in PD. It also considers the wider relevance of abnormal gastric pathology to our current understanding of the etiology of PD. © 2013 International Parkinson and Movement Disorder Society