Abstract
Objective: To evaluate whether there exists distinct characteristics in glucocerebrosidase (GBA)–associated Parkinson disease (PD) with regard to motor and nonmotor symptoms as well as imaging characteristics assessed by transcranial sonography (TCS).
Methods: Twenty patients with PD with heterozygous GBA mutations (N370S, L444P) (GBA-PD) in comparison to 20 patients with sporadic PD negative for GBA mutations (sPD) were included. We assessed motor impairment with the Unified Parkinson’s Disease Rating Scale–III. Nonmotor symptoms were evaluated using the Montreal Cognitive Assessment, Neuropsychiatric Inventory, revised form of the Beck Depression Inventory, Parkinson Disease Sleep Scale, Sniffin’ Sticks, and Unified Multiple System Atrophy Rating Scale items 9–12. TCS imaging was used to detect morphologic characteristics.
Results: Patients with GBA-PD more often had a variety of nonmotor symptoms, namely dementia, neuropsychiatric disturbances, and autonomic dysfunction, and had more severe cases, than patients with sPD. They also demonstrated a higher prevalence of a reduced echogenicity of the brainstem raphe assessed by TCS.
Conclusions: Especially nonmotor symptoms seem to be very common in GBA-PD. Further studies are needed to validate these observations in order to better understand the pathogenesis of GBA-PD and develop specific therapeutic concepts.
Heterozygous mutations in the gene glucocerebrosidase (GBA) are associated with Parkinson disease (PD), representing the most common genetic risk factor for this disorder so far.1,2
Clinically, GBA mutation carriers present with an earlier age at onset and a higher prevalence of cognitive impairment compared to nonmutation carriers.3 Furthermore, single cases with atypical manifestations similar to multiple system atrophy (MSA) and Lewy body dementia (LBD) have been reported.3,4 Genotype–phenotype correlations revealed different phenotypes in patients with PD with severe (e.g., L444P) vs mild (e.g., N370S) GBA mutations, indicating severe mutations to predispose to an earlier age at onset and more frequent cognitive decline.5,6
Here, we report on motor performance, cognitive impairment, neuropsychiatric symptoms, sleep disturbances, autonomic dysfunctions, and olfactory impairment in a sample of 20 patients with PD positive for the 2 most common GBA mutations (N370S, L444P) in comparison to 20 patients with sporadic PD matched for sex and disease duration. We further assessed imaging characteristics using transcranial sonography (TCS).
Since Gaucher disease shows an enormous clinical variation and patients with PD positive for heterozygous mutations in some cases present with an atypical manifestation, we hypothesized that GBA mutation carriers present a different phenotype compared to patients with sporadic PD.
METHODS
Mutational screening.
In preparation for this study, we investigated DNA from 1,000 patients initially diagnosed with idiopathic PD. Mutational screening for 2 of the most common mutations of the GBA gene (N370S, L444P) was performed by genotyping with restriction enzyme digest. Primers and conditions are available upon request.
Subjects.
A total of 33 patients with PD heterozygous for one of the 2 GBA mutations (N370S, L444P) (GBA-PD) from all over Germany were identified. Of those, 20 patients with GBA-PD (6 N370S, 14 L444P) gave informed consent for clinical investigations and were included in this study. To evaluate potential disease specific characteristics of GBA-PD, 20 patients with sporadic PD (sPD) controlled to have none of the 2 GBA mutations and matched for sex and disease duration were included for comparison.
Clinical investigations.
The diagnosis of PD was defined according to the UK Brain Bank Criteria.7 We assessed severity of motor symptoms using the motor part of the Unified Parkinson’s Disease Rating Scale (UPDRS-III).8 Stage of the disease was categorized according to the modified Hoehn & Yahr scale (H&Y).9 Cognitive function was tested by the Montreal Cognitive Assessment (MoCA). A cutoff of <26 out of 30 points indicated cognitive impairment.10 Neuropsychiatric disturbances were assessed using the Neuropsychiatric Inventory (NPI),11 a questionnaire answered by a caregiver of the patient. To optimize understanding of medical terms, the NPI was carried out as a personal interview between neurologist and caregiver. The revised form of the Beck Depression Inventory (BDI-II) was used to detect mood disturbances. The cutoffs were set as follows12: 0–8, no depression; 9–13, minimal depression; 14–19, mild depression; 20–28, moderate depression; 29–63, severe depression. The Parkinson Disease Sleep Scale (PDSS), a 15-item scale on which higher scores indicate greater impairment, was used to evaluate sleep disturbances.13 Olfactory dysfunction was detected using Sniffin’ Sticks.14 A cutoff of <9 (<75%) of 12 odors indicated hyposmia. Subjects with respiratory allergies or infections were excluded from this test. We evaluated autonomic function rating items 9–12 (orthostatic, urinary, sexual, and bowel function) of the Unified Multiple System Atrophy Rating Scale (UMSARS).15
Transcranial sonography.
TCS was performed by an examiner blinded to the mutational status of the patients. We used a phased-array ultrasound system equipped with a 2.5-MHz transducer (Sonoline Elegra; Siemens). The brainstem, basal ganglia, and ventricles were assessed at standardized axial scanning planes as described earlier in detail.16 Hyperechogenicity of the substantia nigra (SN) was defined as a planimetrically measured larger area of increased echogenicity at the anatomic site of the SN than found in 90% of the healthy population. Echogenicity of the brainstem raphe was rated as reduced if the echosignals of the raphe were interrupted or missing on the scanning of both sides despite clear visibility of the red nucleus.16
Statistics.
Statistical analysis was performed using SPSS 17.0 for Windows (SPSS, Chicago, IL). Normal distribution of variables was verified using the Kolmogorov-Smirnov test (p ã 0.05). For variables with normal distribution, we applied the Student t test; for all other variables including ordinal scaled ones the Mann-Whitney U test was performed. Dichotomous data were analyzed using the χ2 test.
Analysis of GBA subgroups.
All assessments were used analogically for the analysis of the 2 GBA subgroups (6 N370S vs 14 L444P). Statistics were performed nonparametrically using the Mann-Whitney U test.
Standard protocol approvals, registrations, and patient consents.
The study was approved by the Ethics Committee of the Faculty of Medicine at the University of Tübingen (497/2009BO1). All participants gave written informed consent.
RESULTS
Demographic and clinical data.
The 2 patient groups were matched for sex (p =0.744) and disease duration (GBA-PD=9.85 years, sPD=9.85 years, p =1.0). A trend of significance was reached in terms of an earlier age at onset and more severe motor impairment in GBA-PD compared to sPD.
Cognitive impairment was more frequent (45% vs 30%) and more severe (22.53 vs 26.53 points) in GBA-PD compared to sPD (p =0.02).
Neuropsychiatric evaluation revealed higher scores for the items depression (p =0.013), anxiety disorder (p =0.007), apathy and indifference (p =0.043), sleep disturbances (p =0.003), as well as appetite and eating abnormalities (p =0.017) with respect to frequency and severity in GBA-PD. Consequently, GBA-PD scored higher in the BDI (12.05) compared to sPD (7.10) (p =0.031) and more frequently scored above the cutoff indicating depression (70% vs 25%, p =0.004).
Severity of distinct autonomic disturbances was more prominent in GBA-PD (orthostatic symptoms p =0.001, urinary function p =0.046, sexual function p =0.026, bowel function p =0.020); see the table and the figure.
Overview of demographic, motor, nonmotor, and imaging characteristics in GBA-PD vs sPDa
Transcranial sonography.
Both GBA-PD and sPD showed a comparable degree of SN hyperechogenicity. Sixty-nine percent of subjects with GBA-PD demonstrated an interrupted brainstem raphe whereas only 21% of patients with sPD showed this phenomenon (p =0.006). The ventricular system and the basal ganglia appeared similar in size and echogenicity in both groups.
GBA subgroups.
Presumably, due to the small and unequally distributed sample size, no significant differences of clinical or imaging data were found in the GBA subgroup analysis (N370S vs L444P).
DISCUSSION
We here present an extensive and detailed description of GBA-associated PD focusing not only on motor but also on a large variety of nonmotor characteristics in comparison to patients with sporadic PD matched for sex and disease duration. We decided to match for disease duration, as both motor and nonmotor features are primarily influenced by the duration of symptoms and to a lesser degree by age. We think this is an applicable purpose if different patient groups present within a similar range of age and age at onset. This might be different in early-onset PD as known from recessively inherited forms in which the young age and age at onset may have an important impact on the course of disease. GBA-PD showed a tendency to an earlier mean age at onset and a more severe motor impairment, as reported previously.3
Prevalence studies on dementia in sporadic PD suggest about 24%–31% of patients to have dementia.17 In our study, 45% of patients with GBA-PD presented with dementia whereas the proportion in sPD (30%) resembled the numbers reported previously.17 Correspondingly, as described by others,2,3 our results demonstrate that GBA-associated PD is more frequently and to a greater extent accompanied by dementia. This fact is of importance since cases initially diagnosed with Lewy body dementia have been reported to have GBA mutations.4 Plausible explanations come from histopathologic studies. Lewy body pathology is hypothesized to be the main substrate forcing the progression of cognitive decline in PD.18 Accordingly, brains from patients with PD with GBA mutations revealed more diffuse neocortical Lewy body-type pathology compared to those from patients with sporadic PD matched for age, sex, and disease duration.3
Furthermore, GBA-PD exhibited a higher prevalence and severity of neuropsychiatric characteristics (depression, apathy, indifference, and anxiety disorder). Whether and to what extent the widespread Lewy pathology that also includes limbic brain structures might help to explain these findings remains to be elucidated.
The more pronounced autonomic impairment in GBA-PD is also noteworthy since single cases of GBA–associated PD were reported to present with a multiple system atrophy–like phenotype.3
Several TCS studies suggest that reduced echogenicity of the midbrain raphe reflects an alteration of the serotonergic system, which is associated with depression as well as urinary incontinence.19,–,23 Therefore, the more frequent morphologic alteration of the midbrain raphe in GBA-PD corresponds to the clinically observed more frequent and more severe impairment of neuropsychiatric and autonomic disturbances. Both GBA-PD and sPD showed marked hyperechogenicity of the substantia nigra, a typical marker for a vulnerability to PD, detected in the majority of sporadic as well as monogenetic cases so far,16 indicating that both forms share common characteristic features regarding substantia nigra pathology and its impact on ultrasound reflection.
Patients with GBA-PD suffer more often and more severely from a variety of nonmotor symptoms than do patients with sPD. Imaging characteristics assessed with TCS might represent morphologic markers corresponding to some of these clinical findings. In contrast to previous studies in which data were collected retrospectively, our patients were examined according to predefined standardized procedures cross-sectionally. Knowledge on prevalence and progression of motor and nonmotor symptoms is of importance to evaluate the effect of therapeutic strategies. However, we regard our findings first of all as an important basis for further studies.
We suggest that findings reported here need to be validated in larger cohorts and patients need to be followed longitudinally to determine the progression of symptoms. Also, the time of onset of nonmotor characteristics needs to be established more accurately, possibly in not yet motorically affected GBA mutation carriers to define markers for the premotor phase of the disease in this subgroup of PD. In addition, further studies are needed to answer the question on how mutant GBA increases the risk for developing PD and how mutations in this specific gene contribute to a widespread Lewy body pathology. We hope that detailed evaluation of clinical data will help to establish more specific phenotypes in PD to better understand pathogenesis and develop specific therapeutic concepts.
AUTHOR CONTRIBUTIONS
K.B., K.S., and D.B. designed the study. K.B., K.S., C.S., I.C., and A.K.H. obtained the data. K.B. and K.S. performed the statistical analysis. K.B. wrote up the first manuscript. All authors were involved in interpretation of the data and critical revision of the manuscript and all authors gave their final approval. D.B. and T.G. supervised the study.
ACKNOWLEDGMENT
The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement 241791 European Project on Mendelian Forms of Parkinson’s Disease (MEFOPA).
DISCLOSURE
Dr. Brockmann has received speaker honoraria from GlaxoSmithKline and Orion Corporation and funding for travel from GlaxoSmithKline, UCB, and the Movement Disorders Society. Dr. Srulijes has received speaker honoraria from Teva Pharmaceutical Industries Ltd. A.-K. Hauser reports no disclosures. Dr. Schulte has received funding for travel from GlaxoSmithKline, UCB, and the Movement Disorders Society. Dr. Csoti has received speaker honoraria from Boehringer Ingelheim, Teva Pharmaceutical Industries Ltd., Lundbeck Inc., UCB, Orion Corporation, GlaxoSmithKline, and Desitin Pharmaceuticals, GmbH; and has served on a scientific advisory board for Novartis. Prof. Gasser serves on the editorial boards of Parkinsonism and Related Disorders, Movement Disorders, and Journal of Neurology; holds a patent re: KASPP (LRRK2) gene, its production and use for the detection and treatment of neurodegenerative diseases; serves as a consultant for Cephalon, Inc. and Merck Serono; serves on speaker’s bureaus of Novartis, Merck Serono, Schwarz Pharma, Boehringer Ingelheim, and Valeant Pharmaceuticals International; and receives research support from Novartis, the European Union, BMBF (the Federal Ministry of Education and Research), and Helmholtz Association. Prof. Berg has served on scientific advisory boards for Novartis, UCB/Schwarz Pharma, GlaxoSmithKline, and Teva Pharmaceutical Industries Ltd.; has received funding for travel or speaker honoraria from Boehringer Ingelheim, Lundbeck Inc., Novartis, GlaxoSmithKline, UCB/Schwarz Pharma, Merck Serono, Johnson & Johnson, and Teva Pharmaceutical Industries Ltd.; and has received research support from Janssen, Teva Pharmaceutical Industries Ltd., Solvay Pharmaceuticals, Inc./Abbott, Michael J Fox Foundation, BMBF, dPV (German Parkinson’s Disease Association), and Center of Integrative Neurosciences.
Footnotes
-
- BDI-II=
- revised form of the Beck Depression Inventory;
- GBA=
- glucocerebrosidase;
- H&Y=
- Hoehn & Yahr scale;
- LBD=
- Lewy body dementia;
- MoCA=
- Montreal Cognitive Assessment;
- MSA=
- multiple system atrophy;
- NPI=
- Neuropsychiatric Inventory;
- PD=
- Parkinson disease;
- PDSS=
- Parkinson Disease Sleep Scale;
- SN=
- substantia nigra;
- sPD=
- sporadic Parkinson disease;
- TCS=
- transcranial sonography;
- UMSARS=
- Unified Multiple System Atrophy Rating Scale;
- UPDRS-III=
- motor part of the Unified Parkinson’s Disease Rating Scale
- Received December 7, 2010.
- Accepted March 31, 2011.
- Copyright © 2011 by AAN Enterprises, Inc.
REFERENCES
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