Glucocerebrosidase Gene L444P mutation is a risk factor for Parkinson's disease in Chinese population

An association between mutations in the glucocerebrosidase (GBA) gene and Parkinson's disease (PD) has been reported in several populations. We searched for four common GBA mutations (L444P, F213I, R353W, and N370S) in 402 Chinese PD patients and 413 age‐ and sex‐matched controls. In the PD cohort, 11 patients were found carrying a heterozygous GBA mutation and all of them had the L444P mutation. Heterozygous GBA mutations were detected none in controls. The GBA gene L444P mutation was detected at a significantly higher frequency among PD patients (11/402 = 2.74%), when compared with the control group (0/413): P = 0.0007. To evaluate the possible role of the GBA gene L444P mutation in PD in Ashkenazi Jewish and non‐Jewish populations, we conducted a meta‐analysis on the topic. In the Chinese population, the GBA gene L444P mutation was detected at a significantly higher frequency among PD patients, when compared with the control group: Z = 3.83, P = 0.0001, OR = 8.42, confidence interval = 95%, 2.83–25.06. In the non‐Jewish populations, the difference was obviously significant: Z = 5.76, P < 0.00001, OR = 8.82, confidence interval = 95%, 4.21–18.48. The results suggest that the GBA gene L444P mutation appears to be a risk factor for PD in Chinese population. © 2010 Movement Disorder Society     

Lysosomal storage disorders and Parkinson's disease: Gaucher disease and beyond

Parkinson's disease is associated with mutations in the glucocerebrosidase gene, which result in the enzyme deficiency causing Gaucher disease, the most common lysosomal storage disorder. We have performed an exhaustive literature search and found that additional lysosomal storage disorders might be associated with Parkinson's disease, based on case reports, the appearance of pathological features such as α‐synuclein deposits in the brain, and substantia nigra pathology. Our findings suggest that the search for biochemical and cellular pathways that link Parkinson's disease with lysosomal storage disorders should not be limited exclusively to changes that occur in Gaucher disease, such as changes in glucocerebrosidase activity or in glucosylceramide levels, but rather include changes that might be common to a wide variety of lysosomal storage disorders. Moreover, we propose that additional genetic, epidemiological, and clinical studies should be performed to check the precise incidence of mutations in genes encoding lysosomal proteins in patients displaying Parkinson's symptoms. © 2011 Movement Disorder Society     

Premotor Parkinson's disease: Clinical features and detection strategies

In many areas of medicine, the focus has shifted from treating existing disease to screening and prevention. The technology to screen for Parkinson's disease (PD) already exists. The current challenge is to define the appropriate use of predictive testing for PD. Imaging technologies currently offer the highest degree of accuracy for identifying premotor PD, but they are expensive as screening tools. Efficiency is greatly enhanced by combining imaging with a prescreening test, such as olfactory testing. This two‐step process has the potential to greatly reduce costs while retaining diagnostic accuracy. Ultimately, the role of preclinical detection of PD will be determined by the ability of emerging therapies to influence clinical outcomes. As such, implementation of large‐scale screening strategies awaits the arrival of clearly safe and effective therapies that address the underlying pathogenesis of PD. Current research to evaluate efficient screening methods and to understand the clinical and physiological features of “premotor” PD will lay the foundation for the screening and prevention strategies of the future. © 2008 Movement Disorder Society     

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. © 2012 Movement Disorder Society     

Parkinson's disease and aging: Same or different process?

Parkinson's disease (PD), which probably commences in the olfactory bulb and nuclei of IX and X, may represent accelerated normal aging or a disease specific process. The olfactory and motor disorders are associated in PD, so that smell loss should reflect the underlying disease course. Information on age‐associated decline can be obtained by single measurement from cross‐sectional analysis of patients and controls of different ages, because the observed between‐subject picture may reflect a similar within‐subject pattern. University of Pennsylvania Smell Identification Test (UPSIT) scores were examined for aging effects in 263 controls and 266 PD patients. Three models were applied that are (a) simple linear regression and (b) quadratic term in age: (i) assuming two parallel curves and (ii) allowing for two separate curves. Both groups declined with age. All three models were fitted successfully to the cross‐sectional data and none suggested that the lower mean UPSIT score in patients compared to controls was a premature ageing effect. The mean PD‐UPSIT score even at the age of 40, was lower than the control mean at the upper life‐span limit, implied that the decline in olfaction in PD is faster than simple aging. Extrapolation back in time suggested onset before birth, which is unlikely and implies that at some point there is a more rapid decline than observed in this sample. On the basis of olfactory measurement, our data are consistent with the proposal that PD starts as an acute event, followed by further disease progression more rapid than simple aging. © 2007 Movement Disorder Society     

Midbrain transcranial sonography in Korean patients with Parkinson's disease.

Transcranial sonography (TCS) is potentially useful for the diagnosis of Parkinson's disease (PD). However, studies on TCS have so far been restricted to European populations. To investigate the efficacy of TCS in Korean PD patients and its correlation with the clinical features, we carried out midbrain TCS in 43 PD patients and 35 normal controls and evaluated the area of the substantia nigra (SN) hyperechogenicity and its ratio to the area of the whole midbrain. In 16 subjects (21%), TCS was unsuccessful due to insufficient acoustic temporal bone windows. The mean area of bilateral SN hyperechogenicity and its ratio to the midbrain area were greater in the PD patients than that in the controls (P < 0.01). In the PD patients, the area of SN hyperechogenicity and its ratio to the individual midbrain area were moderately correlated with the PD duration (r = 0.526 and 0.536, P = 0.01, respectively) but not with the age, UPDRS motor scores or H-Y stage. There was no difference in the SN hyperechogenicity between the tremor-dominant, akinetic-rigid, and mixed-type PD patients. In conclusion, midbrain TCS is an effective diagnostic tool for detecting PD in the Korean population. However, it does not reflect the severity or phenotypes of parkinsonism.     

Glucocerebrosidase gene mutations are associated with Parkinson's disease in southern Italy

Recent studies have reported an association between the glucocerebrosidase (GBA) gene and Parkinson's disease (PD). To elucidate the role of this gene in our population, we screened 395 PD patients and 483 controls from southern Italy for the N370S and the L444P mutations. We found 11 patients (2.8%) carrying a heterozygous mutant GBA allele, whereas only one control subject (0.2%) had a heterozygous substitution (P = 0.0018). These results strongly suggest that Italian carriers of a GBA mutation have an increased risk of developing PD. © 2007 Movement Disorder Society     

Imaging nigral pathology and clinical progression in Parkinson's disease

The pattern of dopamine cell loss in Parkinson's disease (PD) is known to be prominent in the ventrolateral and caudal substantia nigra (SN), but less severe in the dorsal and rostral region. Both diffusion tensor imaging (DTI) and R2* relaxometry of the SN have been reported as potential markers for PD, but their relative ability to mark disease progression and differences in pathophysiological bases remains unclear. High‐resolution T2‐weighted, R2*, and DTI were obtained from 28 controls and 40 PD subjects [15 early stage [disease duration ≤1 year], 14 mid stage [duration 2–5 years], and 11 late stage [duration >5 years]). Fractional anisotropy and R2* values in both rostral and caudal SN were obtained for all subjects, and clinical measures (e.g., disease duration, levodopa‐equivalent daily dosage, and “off”‐drug UPDRS motor score) were obtained for Parkinson's subjects. There was no correlation between fractional anisotropy and clinical measures, whereas R2* was strongly associated with disease progression. Compared to controls, fractional anisotropy in caudal SN was significantly decreased in PD patients of all stages, whereas in rostral SN, it was decreased significantly only in the late‐stage group. R2* in both SN regions was significantly increased in the mid‐ and late‐stage, but not early‐stage, of PD subjects. These findings suggest that fractional anisotropy changes may mark early pathological changes in caudal SN, whereas the changes in R2* may more closely track PD's clinical progression after symptom onset. © 2012 Movement Disorder Society     

The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson's disease

Gaucher disease(GD),the commonest lysosomal storage disorder,results from the lack or functional deficiency of glucocerebrosidase(GCase) secondary to mutations in the GBA1 gene.There is an established association between GBA1 mutations and Parkinson's disease(PD),and indeed GBA1 mutations are now considered to be the greatest genetic risk factor for PD.Impaired lysosomal-autophagic degradation of cellular proteins,including α-synuclein(α-syn),is implicated in the pathogenesis of PD,and there is increasing evidence for this also in GD and GBA1-PD.Indeed we have recently shown in a Drosophila model lacking neuronal GCase,that there are clear lysosomal-autophagic defects in association with synaptic loss and neurodegeneration.In addition,we demonstrated alterations in mechanistic target of rapamycin complex 1(mTORC1) signaling and functional rescue of the lifespan,locomotor defects and hypersensitivity to oxidative stress on treatment of GCase-deficient flies with the mT OR inhibitor rapamycin.Moreover,a number of other recent studies have shown autophagy-lysosomal system(ALS) dysfunction,with specific defects in both chaperone-mediated autophagy(CMA),as well as macroautophagy,in GD and GBA1-PD model systems.Lastly we discuss the possible therapeutic benefits of inhibiting mT OR using drugs such as rapamycin to reverse the autophagy defects in GD and PD.     

Parkinsonism in Gaucher's disease type 1: Ten new cases and a review of the literature

Parkinsonism has been described in patients with Gaucher's disease (GD). We reviewed the 10 cases of patients with both parkinsonism and GD recorded in the French national GD registry, as well as 49 previously published cases. Relative to the general population, parkinsonism in GD patients (1) was more frequent, (2) occurred at an earlier age, (3) responded less well to levodopa, and (4) was more frequently associated with signs of cortical dysfunction. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) were ineffective on GD‐associated parkinsonism, suggesting that parkinsonism itself is not an indication for ERT or SRT in this setting. © 2009 Movement Disorder Society     

Serum lipid alterations in GBA-associated Parkinson's disease

IntroductionMutations in the GBA gene, encoding for the lysosomal enzyme glucocerebrosidase, are associated with Gaucher disease. Alterations in plasma sphingolipids have been reported in Gaucher, and similarly in brain extracts in Lewy body disease. As GBA mutations are prevalent risk factors for Parkinson's disease and overlap of molecular pathways are presumable, here we assessed the lipid profiles in Parkinson's patients with and without GBA mutations.MethodsWe sequenced all GBA exons in 415 Parkinson's patients, previously genotyped for LRRK2. 64 patients (29 GBA positive vs. 35 non-GBA-carriers including 18 LRRK2 positive and 17 non-mutated) were analyzed for chitotriosidase activity and for the concentration of 40 lipid classes using HPLC-MS.Results29/415 patients (6.9%) carried 8 different GBA mutations associated with Gaucher or Parkinson's, including one novel mutation. Chitotriosidase activity was similar across the genetic groups, while the levels of key lipids were altered in GBA mutation carriers: Monohexosylceramide, Ceramide and Sphingomyelin were elevated; while Phosphatidic acid (PA), Phosphatidylethanolamine (PE), Plasmalogen phosphatidylethanolamine (PEp) and Acyl Phosphatidylglycerol (AcylPG) were decreased.ConclusionThe results suggest an important role for these lipids in GBA mediated Parkinson's disease and assist in the identification of common pathways between Gaucher and Parkinson's. Ultimately, our findings may lead to the identification of novel biomarkers for individuals at increased risk of developing Parkinson's disease.     

Transcranial brain sonography in Parkinson's disease with restless legs syndrome

Substantia nigra (SN) hyperechogenicity assessed by transcranial brain sonography (TCS) is a characteristic finding in idiopathic Parkinson's disease (PD). In contrast, SN hypoechogenicity on TCS has been recently demonstrated in restless legs syndrome (RLS). RLS is one of the most common sleep problems in PD, but the pathophysiologic relationship between these two disorders has not been thoroughly elucidated. We compared the SN echogenicities of PD patients with and without RLS to investigate whether comorbid RLS in PD affects SN echogenicity and to explain the echogenic differences between idiopathic RLS (iRLS) and secondary PD–related RLS (pRLS). Sixty‐three PD patients (median age 64.6 ± 10.6 years), 40 iRLS patients (53.1 ± 11.7 years), and 40 healthy controls (69.1 ± 2.3 years) were enrolled in our study. All subjects answered a sleep questionnaire and underwent TCS. PD patients were subdivided into two groups, PD with RLS (PD+RLS, n = 26) and PD without RLS (PD‐RLS, n = 37), and the sonographic findings of each group were compared. Although significant hyperechogenicity was detected in both the SN and SN/midbrain ratios in both PD subgroups compared with the controls and the iRLS group (P < 0.001), there were no significant differences in SN echogenicity between the PD+RLS and PD‐RLS groups. Meanwhile, iRLS patients showed significant SN hypoechogenicity. In conclusion, comorbid RLS in PD did not have an impact on the sonographic SN findings. These results suggest that the pathogenesis of pRLS and iRLS involve different mechanisms. Further study will be required to clarify the association between RLS and PD. © 2010 Movement Disorder Society     

Substantia nigra hyperechogenicity as a marker of predisposition and slower progression in Parkinson's disease.

Increased echogenic size (hyperechogenicity) of the substantia nigra (SN) is a characteristic transcranial sonography finding in patients with Parkinson's disease (PD). The SN echogenic size does not change in the course of the disease. In order to see whether this stable ultrasound marker may give any implications for the rate of PD progression, we sonographically investigated 16 PD patients in whom the rate of progression had been determined by serial 18-fluorodopa positron emission tomography over a follow-up period of 65.7+/-26.7 months. We found a significant negative correlation between the right-to-left averaged SN echogenic size and the rate of disease progression in the caudate nucleus and in the putamen. There was a tendency towards a younger age at symptom onset in patients with SN hyperechogenicity. It may therefore be hypothesized that a differing influence of factors determining SN echogenicity early in life and impairing forces occurring later in life may account for different pathogenetic subgroups of idiopathic PD.     

Predictive value of transcranial sonography in the diagnosis of Parkinson's disease.

Transcanial sonography (TCS) is increasingly applied in the diagnosis of Parkinson's disease (PD), but investigator bias may influence the results of examination. Blinding the sonographer to the clinical diagnosis of 42 PD patients and 35 controls, we obtained a positive predictive value of 85.7% and a negative predictive value of 82.9% in the diagnosis of PD solely by interpreting the results of TCS, indicating that TCS is a valuable additional tool in the diagnosis of PD.