Mya C. Schiess

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.

Levodopa slows prosaccades and improves antisaccades: an eye movement study in Parkinson’s disease

Background: The integrity of frontal systems responsible for voluntary control and their interaction with subcortical regions involved in reflexive responses were studied in patients with Parkinson’s disease (PD). Previous studies have shown that patients with PD have impaired executive function, including deficits in attention, motor planning and decision making. Methods: Executive function was measured through eye movements: reflexive (stimulus driven) prosaccades and voluntary (internally guided) antisaccades. Patients with advanced idiopathic PD, off and on their optimal levodopa therapy, were tested on a prosaccade and an antisaccade task and compared with matched controls. Results: Levodopa significantly increased response time for reflexive prosaccades and reduced error rate for voluntary antisaccades. Conclusions: Consistent with our proposed model, patients with PD in the medicated state are better able to plan and execute voluntary eye movements. These findings suggest levodopa improves function of the voluntary frontostriatal system, which is deficient in PD.

Benign tremulous parkinsonism.

BACKGROUND Benign tremulous parkinsonism has never been precisely defined nor has the long-term course been studied. OBJECTIVE To report the clinical features and longitudinal course of patients with benign tremulous parkinsonism encountered in our movement disorders practice. DESIGN Computer search of medical records database. SETTING Mayo Clinic, Rochester, Minn. PATIENTS Of 116 patients identified, 16 (10 male and 6 female) had at least an 8-year history of this disease, had been examined by a senior movement disorders specialist, and had ultimately been diagnosed as having benign tremulous parkinsonism after an initial diagnosis of Parkinson disease (PD). INTERVENTIONS None. MAIN OUTCOME MEASURES Age at onset of disease, response to levodopa therapy, tremor characteristics, and family history. RESULTS Mean disease duration was 11 years (range, 8-25 years) at last follow-up. Mean age at onset, 58.5 years, was younger than in most PD series, and most patients had a poor levodopa response (although levodopa trials were inadequate in some). A moderate to marked postural tremor was noted in 13 of the 16 patients, including 6 with a kinetic tremor. A family history of PD and/or tremor was reported in 10 (63%) of our patients. Three patients required thalamic deep brain surgery to treat their tremor. CONCLUSIONS Benign tremulous parkinsonism may be a distinct clinical entity characterized by tremor predominance plus minimal progression of other aspects of parkinsonism. The tremor is often not very responsive to levodopa therapy. In this series, most patients had immediate family members with a diagnosis of tremor or PD.

Parkinson's disease subtypes: clinical classification and ventricular cerebrospinal fluid analysis

The current study presents preliminary data regarding the development and validation of a rating system designed to classify PD patients into clinical subgroups. Using portions of the Unified Parkinsons Disease Rating Scale, a ratio value was derived, yielding three patient subtypes: a tremor-dominant group (T), an akinetic-rigid group (AR), and a mixed group (MX). Validation of the schema was conducted by grouping PD surgical candidates into specific disease subtypes and evaluating differences in neurotransmitter profiles among disease subtypes and non-PD neurological controls. High pressure liquid chromatography analysis of ventricular cerebrospinal fluid indicated 5-hydroxyindoleacetic acid was significantly lower in the AR and MX groups compared to non-PD controls; whereas, glycine was significantly higher in the AR group compared to the T, MX, and control groups. The results suggest that an operational approach can be utilized to differentiate between PD subtypes with distinct neurochemical profiles.

Estrogen priming affects active membrane properties of medial amygdala neurons

The medial nucleus of the amygdala (MNA) in the rat is a target tissue for estrogen binding and a sexually dimorphic structure. We used an in vivo slice preparation and intracellular recording techniques to study the effects of beta-estradiol priming on active and passive membrane properties of MNA neurons. Two groups of adult female rats were used; ovariectomized (OVX) non-primed rats and OVX rats that were estrogen-primed at least 24 h prior to recording. Estrogen priming increased the occurrence of spontaneous excitatory postsynaptic potentials (EPSPs) in MNA neurons, and of depolarizing afterpotentials (DAPs) observed with a cathodally triggered action potential, and was associated with a lack of accommodation in these cells. Overall, long-term exposure to estrogen markedly increased the spontaneous activity and excitability of the MNA neurons.

Characterization of the electrophysiological and morphological properties of rat central amygdala neurons in vitro

Forty central amygdala neurons labelled with 2% Neurobiotin were categorized according to their distinctive bioelectrical membrane properties and classified physiologically by their hyperpolarized resting membrane potential (−74 mV), short duration medium afterhyperpolarization (239.2 ms), and non‐accommodating response as Type A neurons (63%; N = 25/40), or as Type B neurons (37%; N = 15/40) by their depolarized resting membrane potential (‐66 mV), long slow‐afterhyperpolarization (1.8 s), and accommodation response. Visualized within subnuclei of the central amygdala, Neurobiotin‐labelled Type A neurons were medium‐size cells [16.5 ± 3 × 10.7 ± 2 μm; length × width] with smooth, spine‐free ovoid, pyramiform, and fusiform perikarya. Aspinous primary dendrites gave rise to distal dendrites covered with numerous small pedunculated spines; density of spines ranged from sparse to abundant. Type B central amygdala neurons were larger cells [23.9 ± 5 × 14.9 ± 4 μm] with smooth, aspinous ovoid, polygonal, and pyramiform somata. Dendrites were aspinous and covered with variably sized varicosities. Two distinct populations of neurons exist within the central amygdaloid complex: the medium‐size, spine‐laden Type A defined neuron with its non‐accommodating electrophysiological response and the larger aspinous, varicosity‐laden Type B defined neuron with its accommodating response. In contrast to their neighboring “cortical‐like” amygdala neurons, central amygdala neurons possess a “striatal‐like” cytoarchitecture and electrophysiology. J. Neurosci. Res. 58:663–673, 1999.

Altered nigrostriatal and nigrocortical functional connectivity in rapid eye movement sleep behavior disorder

STUDY OBJECTIVES Rapid eye movement sleep behavior disorder (RBD) is a condition closely associated with Parkinson disease (PD). RBD is a sleep disturbance that frequently manifests early in the development of PD, likely reflecting disruption in normal functioning of anatomical areas affected by neurodegenerative processes. Although specific neuropathological aspects shared by RBD and PD have yet to be fully documented, further characterization is critical to discovering reliable biomarkers that predict PD onset. In the current study, we tested the hypothesis of altered functional connections of the substantia nigra (SN) in patients in whom RBD was diagnosed. DESIGN Between-groups, single time point imaging. SETTING UTHSC-H 3 telsa MRI center. PARTICIPANTS Ten patients with RBD, 11 patients with PD, and 10 age-matched controls. INTERVENTIONS NA. MEASUREMENTS AND RESULTS We measured correlations of SN time series using resting state blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) in patients with idiopathic RBD who were at risk for developing PD, patients in whom PD was diagnosed, and age-matched controls. Using voxelwise analysis of variance, different correlations (P < 0.01, whole-brain corrected) between left SN and left putamen were found in patients with RBD compared with controls and patients with PD. SN correlations with right cuneus/precuneus and superior occipital gyrus were significantly different for patients with RBD compared with both controls and patients with PD. CONCLUSIONS The results suggest that altered nigrostriatal and nigrocortical connectivity characterizes rapid eye movement sleep behavior disorder before onset of obvious motor impairment. The functional changes are discussed in the context of degeneration in dopaminergic and cognition-related networks.

α-Synuclein and Anti-α-Synuclein Antibodies in Parkinson’s Disease, Atypical Parkinson Syndromes, REM Sleep Behavior Disorder, and Healthy Controls

α-synuclein is thought to play a key role in Parkinson’s disease (PD) because it is the major protein in Lewy bodies, and because its gene mutations, duplication, and triplication are associated with early-onset PD. There are conflicting reports as to whether serum and plasma concentrations of α-synuclein and anti-α-synuclein antibodies differ between PD and control subjects. The objectives of this study were to compare the levels of α-synuclein and its antibodies between individuals with typical PD (n = 14), atypical Parkinson syndromes (n = 11), idiopathic rapid eye movement sleep behavior disorder (n = 10), and healthy controls (n = 9), to assess the strength of association between these serum proteins, and to determine group sizes needed for a high probability (80% power) of detecting statistical significance for 25% or 50% differences between typical PD and control subjects for these measurements. Analysis of log-transformed data found no statistically significant differences between groups for either α-synuclein or its antibodies. The concentrations of these proteins were weakly correlated (Spearman rho = 0.16). In subjects with typical PD and atypical Parkinson syndromes, anti-α-synuclein antibody levels above 1.5 µg/ml were detected only in subjects with no more than four years of clinical disease. Power analysis indicated that 236 and 73 samples per group would be required for an 80% probability that 25% and 50% differences, respectively, in mean α-synuclein levels between typical PD and control subjects would be statistically significant; for anti-α-synuclein antibodies, 283 and 87 samples per group would be required. Our findings are consistent with those previous studies which suggested that serum concentrations of α-synuclein and its antibodies are not significantly altered in PD.

Reduced volume of the putamen in REM sleep behavior disorder patients.

OBJECTIVE The purpose of this study was to quantify volumes of specific subcortical gray matter nuclei implicated in Parkinsons disease (PD) as a preliminary step for identifying a non-invasive clinical biomarker for PD. We hypothesized that REM sleep behavior disorder (RBD) patients, at risk for developing PD, will demonstrate a pattern of neuronal degeneration reflected in reduced striatal volumes on T1-weighted MRI. METHODS We compared measures of RBD patients confirmed by polysomnography (PSG) with groups of age/gender-matched Control subjects and early PD (EPD) patients (Hoehn & Yahr < 2). Clinical measurements included the Unified Parkinsons disease Rating Scales (UPDRS), timed gait and finger tapping tasks, the Parkinsons Disease Questionnaire (PDQ-39), and a time-synchronized video recorded single-night PSG. Volumetric measurements were derived from high-resolution T1-weighted 3 T MRI images. RESULTS The matched Control and EPD groups were statistically similar to the RBD group in age, gender, handedness, and total brain volumes. The RBD group had smaller bilateral putamen volumes (both raw and normalized by brain tissue volume), in addition to some clinical impairment on the UPDRS and PDQ-39. CONCLUSIONS Reduced putamen volumes may be a structural marker for RBD and reflect a pattern of neurodegeneration that predicts the development of PD.

The central nucleus of the rat amygdala: in vitro intracellular recordings

Membrane properties of neurons from the central nucleus of the rat amygdala (ACe) were analyzed using intracellular current-clamp recordings from in vitro coronal slices of adult rat amygdala. Two types of neurons were identified and classified according to their accommodation characteristics and the nature of their afterhyperpolarizations (AHP). Type A neurons represented 74% of the population and were identified by a lack of accommodation and a medium-AHP (m-AHP) in response to transient (100 ms) depolarizing current injection. The m-AHP was defined by a fast decay time constant with a mean tau AHP = 113.6 ms. In both Type A and Type B ACe cells the m-AHP can be reduced with cadmium and rubidium. Type B neurons represented 26% of the population and were identified by the presence of accommodation and a long duration slow-AHP (s-AHP) following the m-AHP. The s-AHP was defined by a slow decay time constant with a mean tau AHP = 1.7 s. The s-AHP was similar to the AHP mediated by IAHP, a long duration calcium-dependent, noradrenaline-sensitive current present in hippocampal neurons. In Type B cells, the s-AHP was reduced by cadmium and noradrenaline. There was no significant difference between Type A and B ACe neurons in passive electrical properties such as the membrane input resistance (RiA = 113 M omega, RiB = M omega), and the membrane time constant (tau A = 15 ms, tau B = 16 ms). However, there was a statistically significant difference in the resting membrane potentials of Type A and B ACe neurons (RMPA = -67 mV; RMPB = -63 mV). These data suggest that the characteristic active membrane properties displayed by Type A and Type B neurons will determine the ability of each type to integrate and encode neuronal information.