Karin Srulijes

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.

Enlarged Substantia Nigra Hyperechogenicity and Risk for Parkinson Disease: A 37-Month 3-Center Study of 1847 Older Persons

OBJECTIVE To evaluate whether enlarged substantia nigra hyperechogenicity (SN+) is associated with an increased risk for Parkinson disease (PD) in a healthy elderly population. DESIGN Longitudinal 3-center observational study with 37 months of prospective follow-up. SETTING Individuals 50 years or older without evidence of PD or any other neurodegenerative disease. PARTICIPANTS Of 1847 participants who underwent a full medical history, neurological assessment, and transcranial sonography at baseline, 1535 could undergo reassessment. MAIN OUTCOME MEASURE Incidence of new-onset PD in relation to baseline transcranial sonography status. RESULTS There were 11 cases of incident PD during the follow-up period. In participants with SN+ at baseline, the relative risk for incident PD was 17.37 (95% confidence interval, 3.71-81.34) times higher compared with normoechogenic participants. CONCLUSIONS In this prospective study, we demonstrate for the first time a highly increased risk for PD in elderly individuals with SN+. Transcranial sonography of the midbrain may therefore be a promising primary screening procedure to define a risk population for imminent PD.

Phosphorylated α-Synuclein in Parkinson’s Disease

An assay for detecting phosphorylated α-synuclein in CSF may help to diagnose Parkinson’s disease and determine disease severity. Tracking the Course of Neurodegeneration Parkinson’s disease (PD), a neurodegenerative disorder characterized by loss of motor function, affects millions of people worldwide. Although there are drugs that can replace dopamine and thus compensate for the loss of dopaminergic neurons of the nigrostriatal pathway, there is no treatment that can prevent neuronal degeneration. A big goal has been to discover biomarkers that could be used to distinguish PD from other parkinsonian disorders, such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and to follow disease progression. To date, one of the most extensively tested markers is α-synuclein, a protein that has been implicated in the pathogenesis of PD. There is a decrease in the concentration of α-synuclein in the cerebrospinal fluid (CSF) of patients with PD compared to healthy individuals. However, α-synuclein does not appear to be useful in terms of differentiating PD from other parkinsonian disorders with overlapping symptoms and does not correlate with PD severity or progression. Now, Wang and colleagues have identified an isoform of α-synuclein, phosphorylated α-synuclein (PS-129), in human CSF that may prove to be a more useful marker of PD than α-synuclein. First, the authors developed a highly sensitive and specific assay to measure PS-129 concentrations as well as total α-synuclein in CSF samples from healthy individuals and from a cohort of patients with PD, MSA, PSP, and Alzheimer’s disease. The authors discovered that the PS-129 concentration in CSF, when combined with the total α-synuclein concentration in CSF, helped to distinguish PD patients from those with MSA and PSP. Additionally, CSF PS-129 concentrations in CSF correlated with disease severity in PD patients. These early results suggest that PS-129 may be useful as a marker to assist in the differential diagnosis of PD and to monitor disease progression. This would be of value for selecting patients for clinical trials to test new PD-modifying therapies as they become available and to monitor disease in response to these treatments. However, before PS-129 can be deployed as a marker for PD, it will need to be validated in independent cohorts of PD patients, especially those with samples collected longitudinally. Phosphorylated α-synuclein (PS-129), a protein implicated in the pathogenesis of Parkinson’s disease (PD), was identified by mass spectrometry in human cerebrospinal fluid (CSF). A highly sensitive and specific assay was established and used to measure PS-129 together with total α-synuclein in the CSF of patients with PD, other parkinsonian disorders such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and healthy individuals (a total of ~600 samples). PS-129 CSF concentrations correlated weakly with PD severity and, when combined with total α-synuclein concentrations in CSF, contributed to distinguishing PD from MSA and PSP. Further rigorous validation in independent cohorts of patients, especially those where samples have been collected longitudinally, will determine whether the concentration of PS-129 in CSF will be useful for diagnosing PD and for monitoring PD severity and progression.

Enlarged hyperechogenic substantia nigra as a risk marker for Parkinson's disease

SN hyperechogenicity (SN+), determined by transcranial sonography, has been proposed as a risk factor for Parkinsons disease (PD). Recently, we reported a 17.4‐fold increased risk for PD in individuals with SN+ older than 50 years within 3 years.

GBA-Associated Parkinson's Disease: Reduced Survival and More Rapid Progression in a Prospective Longitudinal Study

Parkinsons disease (PD) patients with GBA mutations show an earlier age at onset and more severe non‐motor symptoms compared with PD patients without GBA mutations.

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

Screening batteries to narrow down a target‐at‐risk population are essential for trials testing neuroprotective compounds aiming to delay or prevent onset of Parkinsons disease (PD).

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: Richardsons 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 Parkinsons 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.

Clinical and dual‐tasking aspects in frequent and infrequent fallers with progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease with no sufficient therapeutic options to date. Falls are the most devastating feature. The causes of these falls are not well understood. To test the impact of PSP‐associated motor and cognitive features on falls, 26 PSP patients were prospectively recruited and divided into frequent fallers (> one fall/month, 18 patients) and infrequent fallers (≤ one fall/month, 8 patients). Further parameters were assessed by clinical investigation and biomechanical gait and balance analysis with and without dual‐task paradigms. Physical activity was measured through an ambulatory device. Frequent fallers scored higher on the total PSP rating scale and the subscales “history,” “mental,” “bulbar,” “supranuclear ocular motor,” and “gait/midline exam” but not on disease duration, the subscale “limb exam,” the UPDRS motor score and the sway analysis. Frequent fallers also showed an increased probability of an altered walking pattern with shortened step lengths and increased cadence under a dual‐task situation. It is concluded that the occurrence of falls in PSP seems strongly associated with the deterioration of bulbar function, but not relevantly with typical parkinsonian features like rigidity and bradykinesia. The decreased ability to deal with distraction of attention under a dual‐task situation points to a relevant impact of cortical and subcortical dysfunction on the frequency of falls.

GBA-associated PD Neurodegeneration, altered membrane metabolism, and lack of energy failure

Objective: To elucidate possible mechanisms leading to neurodegeneration in patients with glucocerebrosidase (GBA)–associated Parkinson disease (PD) using combined proton (1H) and phosphorus (31P) magnetic resonance spectroscopic imaging (MRSI) in vivo. Methods: 1H and 1H-decoupled 31P MRSI was performed in 13 patients with PD with heterozygous GBA mutations (GBA-PD) and 19 age- and sex-matched healthy controls to investigate metabolite concentrations in the mesostriatal target regions of PD pathology. NAA as marker of neuronal integrity, choline and ethanolamine containing compounds as markers of membrane phospholipid metabolism, and energy metabolites (notably high-energy phosphates) were quantified. Results: Compared to controls, NAA was significantly reduced in the putamen (p = 0.012) and in the midbrain of GBA-PD (p = 0.05). The choline concentration obtained from 1H MRSI was significantly decreased in the midbrain of GBA-PD (p = 0.010). The phospholipid degradation product glycerophosphoethalonamine was increased in the putamen of GBA-PD (p = 0.05). Changes of energy metabolism were not detected in any region of interest. Conclusion: The pattern of neurodegeneration in GBA-associated PD is more pronounced in the putamen than in the midbrain. Our MRSI findings suggest that the neurodegenerative process in GBA-PD is associated with alterations of membrane phospholipid metabolism which might be also involved in abnormal α-synuclein aggregation.

Fluorodeoxyglucose Positron Emission Tomography in Richardson's Syndrome and Progressive Supranuclear Palsy-Parkinsonism

We hypothesized that postural instability and cognitive decline in patients with Richardsons syndrome could be a consequence of reduced thalamic and frontal metabolism. Severe Parkinsonian signs in patients with progressive supranuclear palsy‐parkinsonism may be reflected by alterations in putaminal metabolism.