Patient's perception: shorter and more severe prodromal phase in GBA-associated PD.

BACKGROUND: Prevalence and time of occurrence of prodromal symptoms of Parkinson's disease (PD) in relation to the onset of classical motor manifestation varies between patients. Possible modifying factors might be different genetic architectures predisposing to varying burden of manifestations. OBJECTIVES: To characterize the prodromal phase in PD patients with heterozygous mutations in the GBA gene compared to PD patients without GBA mutation. METHODS: In a retrospective design, 151 participants [47 PD patients carrying a GBA mutation (PDGBA ), 52 idiopathic PD patients (PDidiopathic ), 52 healthy elderly (CON)] underwent a validated structured interview designed to assess prevalence and time of occurrence of prodromal symptoms. RESULTS: PDGBA showed a higher prevalence of prodromal symptoms and almost simultaneous occurrence of non-motor and early motor symptoms shortly before PD diagnosis whereas PDidiopathic reported a longer prodromal phase starting with non-motor symptoms. CONCLUSION: The short and severe prodromal phase in PDGBA might call for shorter assessment intervals in yet premanifest GBA mutation carriers.

GBA-associated parkinsonism and dementia: beyond α-synucleinopathies?

BACKGROUND AND PURPOSE: To date the role of GBA mutations beyond α-synucleinopathies in the parkinsonism-dementia spectrum is still unclear. The aim of the study was to screen for GBA mutations in progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), primary progressive aphasia (PPA) and the behavioural variant of frontotemporal dementia (bvFTD). METHODS: In all, 303 patients with a clinical diagnosis of PSP (n = 157), CBS (n = 39), PPA (n = 35) and bvFTD (n = 72) and 587 neurologically healthy controls were screened for the most common GBA mutations. RESULTS: GBA mutations were detected in one healthy control and four patients with a clinical diagnosis of PSP (n = 1), probable CBS (n = 2) and PPA (n = 1, with concomitant C9orf72 expansion). Overall the prevalence of GBA mutations was low in non-α-synucleinopathies but significantly higher in the CBS subgroup compared to controls. CONCLUSION: Although numbers are small, our findings indicate that the clinical phenotype of GBA-associated neurodegenerative disease is more heterogeneous than previously assumed, including phenotypes not usually associated with underlying α-synucleinopathies. This may be of relevance, once causal therapeutic strategies for GBA-associated neurodegenerative disease are developed.

Differentiation of progressive supranuclear palsy: clinical, imaging and laboratory tools.

Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian syndrome comprising two main clinical subtypes: Richardson's syndrome (RS), characterized by prominent postural instability, supranuclear vertical gaze palsy and frontal dysfunction; and PSP-parkinsonism (PSP-P) which is characterized by an asymmetric onset, tremor and moderate initial therapeutic response to levodopa. The early clinical features of PSP-P are often difficult to discern from idiopathic Parkinson's disease (PD), and other atypical parkinsonian disorders, including multiple system atrophy (MSA) and corticobasal syndrome (CBS). In addition, rare PSP subtypes may be overlooked or misdiagnosed if there are atypical features present. The differentiation between atypical parkinsonian disorders and PD is important because the prognoses are different, and there are different responses to therapy. Structural and functional imaging, although currently of limited diagnostic value for individual use in early disease, may contribute valuable information in the differential diagnosis of PSP. A growing body of evidence shows the importance of CSF biomarkers in distinguishing between atypical parkinsonian disorders particularly early in their course when disease-modifying therapies are becoming available. However, specific diagnostic CSF biomarkers have yet to be identified. In the absence of reliable disease-specific markers, we provide an update of the recent literature on the assessment of clinical symptoms, pathology, neuroimaging and biofluid markers that might help to distinguish between these overlapping conditions early in the course of the disease.

The PRIPS study: screening battery for subjects at risk for Parkinson's disease.

BACKGROUND AND PURPOSE: Screening batteries to narrow down a target-at-risk population are essential for trials testing neuroprotective compounds aiming to delay or prevent onset of Parkinson's disease (PD). METHODS: The PRIPS study focuses on early detection of incident PD in 1847 at baseline PD-free subjects, and assessed age, male gender, positive family history, hyposmia, subtle motor impairment and enlarged substantia nigra hyperechogenicity (SN+). RESULTS: After 3 years follow-up 11 subjects had developed PD. In this analysis of the secondary outcome parameters, sensitivity and specificity of baseline markers for incident PD were calculated in 1352 subjects with complete datasets (10 PD patients). The best approach for prediction of incident PD comprised three steps: (i) prescreening for age, (ii) primary screening for positive family history and/or hyposmia, and (iii) secondary screening for SN+. CONCLUSION: With this approach, one out of 16 positively screened participants developed PD compared to one out of 135 in the original cohort. This corresponds to a sensitivity of 80.0%, a specificity of 90.6% and a positive predictive value of 6.1%. These values are higher than for any single screening instrument but still too low for a feasible and cost-effective screening strategy which might require longer follow-up intervals and application of additional instruments.

GBA-associated PD presents with nonmotor characteristics.

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.