Michelle A. Burack

In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia

Objective: To investigate the specificity of in vivo amyloid imaging with [11C]–Pittsburgh Compound B (PIB) in Parkinson disease dementia (PDD). Methods: We performed detailed neuropathologic examination for 3 individuals with PDD who had PIB PET imaging within 15 months of death. Results: We observed elevated cortical uptake of [11C]-PIB on in vivo PET imaging in 2 of the 3 cases. At autopsy, all 3 individuals had abundant cortical Lewy bodies (Braak PD stage 6), and were classified as low-probability Alzheimer disease (AD) based on NIA-Reagan criteria. The 2 PIB-positive individuals had abundant diffuse Aβ plaques but only sparse neuritic plaques and intermediate neurofibrillary tangle pathology. The PIB-negative individual had rare diffuse plaques, no neuritic plaques, and low neurofibrillary tangle burden. Conclusions: [11C]–Pittsburgh Compound B (PIB) PET is specific for fibrillar Aβ molecular pathology but not for pathologic diagnosis of comorbid Alzheimer disease in individuals with Parkinson disease dementia. The ability to specifically identify fibrillar Aβ amyloid in the setting of α-synucleinopathy makes [11C]-PIB PET a valuable tool for prospectively evaluating how the presence of Aβ amyloid influences the clinical course of dementia in patients with Lewy body disorders.

Amyloid imaging of Lewy body-associated disorders.

Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal β‐amyloid deposition in addition to diffuse Lewy bodies (α‐synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain. The purpose of this study was to determine whether amyloid‐β deposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body‐associated disorders. Nine healthy controls, 8 PD with no cognitive impairment, 9 PD with mild cognitive impairment, 6 DLB, and 15 PDD patients underwent [11C]‐PIB positron emission tomography imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow‐up and postmortem examinations were performed on a subset of participants. Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment. These results suggest that the presence of fibrillar amyloid‐β does not distinguish between clinical subtypes of Lewy body‐associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid‐β may modify the severity of global cognitive impairment in individuals with Lewy body‐associated dementia.

Mechanisms of neuronal polarity

The mechanisms that permit neurons to establish axons and dendrites involve an interplay between a cells genetic program and signals in its environment. Recent experiments have identified some of the important extracellular molecules that regulate dendritic development and have furthered our understanding of the endogenous cell biological mechanisms that underlie protein sorting. Some of the signaling pathways that allow extracellular cues to regulate neuronal morphogenesis are also being elucidated.

Technology in Parkinson's disease: Challenges and opportunities

The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinsons disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide‐scale and long‐term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the “big data” acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open‐source and/or open‐hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self‐adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed‐loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico‐pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease‐modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD.

Sorting and directed transport of membrane proteins during development of hippocampal neurons in culture.

Hippocampal neurons in culture develop morphological polarity in a sequential pattern; axons form before dendrites. Molecular differences, particularly those of membrane proteins, underlie the functional polarity of these domains, yet little is known about the temporal relationship between membrane protein polarization and morphological polarization. We took advantage of viral expression systems to determine when during development the polarization of membrane proteins arises. All markers were unpolarized in neurons before axonogenesis. In neurons with a morphologically distinguishable axon, even on the first day in culture, both axonal and dendritic proteins were polarized. The degree of polarization at these early stages was somewhat less than in mature cells and varied from cell to cell. The cellular mechanism responsible for the polarization of the dendritic marker protein transferrin receptor (TfR) in mature cells centers on directed transport to the dendritic domain. To examine the relationship between cell surface polarization and transport, we assessed the selectivity of transport by live cell imaging. TfR-green fluorescent protein-containing vesicles were already preferentially transported into dendrites at 2 days, the earliest time point we could measure. The selectivity of transport also varied somewhat among cells, and the amount of TfR-green fluorescent protein fluorescence on intracellular structures within the axon correlated with the amount of cell surface expression. This observation implies that selective microtubule-based transport is the primary mechanism that underlies the polarization of TfR on the cell surface. By 5 days in culture, the extent of polarization on the cell surface and the selectivity of transport reached mature levels.

Site-specific regulation of Alzheimer-like tau phosphorylation in living neurons

The microtubule-associated protein tau is more highly phosphorylated at certain residues in developing brain and in Alzheimers disease paired helical filaments than in adult brain. We examined the regulation of tau phosphorylation at some of these sites in rat brain using the phosphorylation state-dependent anti-tau antibodies AT8, Tau1, and PHF1. The AT8 and PHF1 antibodies bind to phosphorylated tau, while Tau1 binds to unphosphorylated tau. Levels of tau reactive for AT8 were high only during the first postnatal week, with levels in adult declining to approximately 5% of the levels in neonates. In neonatal forebrain slices, tau became rapidly dephosphorylated at the AT8 and Tau1 sites during incubation at 34 degrees C, but was incompletely dephosphorylated at the PHF1 site. Dephosphorylation at AT8 sites, but not at Tau1 or PHF1 sites, was completely inhibited by 1 microM okadaic acid. Hence the regulation of tau phosphorylation by okadaic acid-sensitive phosphatase(s) was site-specific. Addition of 1 microM okadaic acid after dephosphorylation at the AT8 locus yielded a partial recovery of AT8 immunoreactivity, and incubation with basic fibroblast growth factor increased phosphorylation at the AT8 site in a dose-dependent manner. These results indicate that endogenously active and basic fibroblast growth factor stimulated tau kinases directed toward an Alzheimers disease-related site were present in the slices. In adult brain slices, the small pool of AT8-reactive tau was remarkably insensitive to dephosphorylation during incubation, and okadaic acid treatment induced only small increases in AT8 immunoreactivity. These results suggest that tau phosphorylation in adult brain is less dynamic than in neonatal brain. These findings indicate that neonatal tau is not only phosphorylated more highly than adult tau, but also more dynamically regulated by protein phosphatases and protein kinases than adult tau. The inability of okadaic acid to induce large increases in tau phosphorylation in adult rat brain slices suggests that a loss of protein phosphatase activity alone would not be sufficient to produce the hyperphosphorylation observed in Alzheimers disease paired helical filaments. Stimulation of kinase activity by basic fibroblast growth factor is likely to modulate tau function during development, and may contribute to the genesis of hyperphosphorylated tau in Alzheimers disease.

Objective motion sensor assessment highly correlated with scores of global levodopa-induced dyskinesia in Parkinson's disease.

BACKGROUND Chronic use of medication for treating Parkinsons disease (PD) can give rise to peak-dose dyskinesia. Adjustments in medication often sacrifice control of motor symptoms, and thus balancing this trade-off poses a significant challenge for disease management. OBJECTIVE To determine whether a wrist-worn motion sensor unit could be used to ascertain global dyskinesia severity over a levodopa dose cycle and to develop a severity scoring algorithm highly correlated with clinician ratings. METHODS Fifteen individuals with PD were instrumented with a wrist-worn motion sensor unit, and data were collected with arms in resting and extended positions once every hour for three hours after taking a levodopa dose. Two neurologists blinded to treatment status viewed subject videos and rated global and upper extremity dyskinesia severity based on the modified Abnormal Involuntary Movement Scale (mAIMS). Linear regression models were developed using kinematic features extracted from motion sensor data and extremity, global, or combined (average of extremity and global) mAIMS scores. RESULTS Dyskinesia occurring during a levodopa dose cycle was successfully measured using a wrist-worn sensor. The logarithm of the power spectrum area between 0.3-3 Hz and the combined clinician scores resulted in the best model performance, with a correlation coefficient between clinician and model scores of 0.81 and root mean square error of 0.55, both averaged across the arms resting and extended postures. CONCLUSIONS One sensor unit worn on either hand can effectively predict global dyskinesia severity during the arms resting or extended positions.

Motion sensor dyskinesia assessment during activities of daily living.

BACKGROUND Dyskinesia throughout the levodopa dose cycle has been previously measured in patients with Parkinsons disease (PD) using a wrist-worn motion sensor during the stationary tasks of arms resting and extended. Quantifying dyskinesia during unconstrained activities poses a unique challenge since these involuntary movements are kinematically similar to voluntary movement. OBJECTIVE To determine the feasibility of using motion sensors to measure dyskinesia during activities of daily living. METHODS Fifteen PD subjects performed scripted activities of daily living while wearing motion sensors on bilateral hands, thighs, and ankles over the course of a levodopa dose cycle. Videos were scored by clinicians using the modified Abnormal Involuntary Movement Scale to rate dyskinesia severity in separate body regions, with the total score used as an overall measure. Kinematic features were extracted from the motion data and algorithms were generated to output severity scores. RESULTS Movements when subjects were experiencing dyskinesia were less smooth than when they were not experiencing dyskinesia. Dyskinesia scores predicted by the model using all sensors were highly correlated with clinician scores, with a correlation coefficient of 0.86 and normalized root-mean-square-error of 7.4%. Accurate predictions were maintained when two sensors on the most affected side of the body (one on the upper extremity and one on the lower extremity) were used. CONCLUSIONS A system with motion sensors may provide an accurate measure of overall dyskinesia that can be used to monitor patients as they complete typical activities, and thus provide insight on symptom fluctuation in the context of daily life.

Neurophysiological correlates of motor and working memory performance following subthalamic nucleus stimulation

Subthalamic nucleus (STN) deep brain stimulation (DBS) has become an accepted treatment for the motor manifestations of Parkinson disease (PD). The beneficial motor effects of STN DBS are likely due to modulation of BG output to frontal cortical regions associated with motor control, but the underlying neurophysiology of STN DBS effects, especially at the level of the cortex, is not well understood. In this study, we examined the effects of STN DBS on motor disability and visual working memory, a cognitive process supported by pFC. We tested 10 PD participants off medications, ON and OFF stimulation, along with 20 normal controls on a visual working memory task while simultaneously recording cortical EEG. In the OFF state, PD patients had poor motor function, were slower and less accurate in performing the working memory task, and had greater amplitudes and shorter latencies of the N200 ERP response. DBS improved clinical motor function, reduced N200 amplitudes, and increased N200 latencies but had little effect on working memory performance. We conclude that STN DBS normalizes neurophysiological activity in fronto striatal circuits and this may independently affect motor and cognitive function.

Selective suppression of in vitro electrographic seizures by low-dose tetrodotoxin: a novel anticonvulsant effect.

Localized injections of 50 microM tetrodotoxin (TTX) in rat hippocampal slices blocked stimulus train-evoked electrographic seizures (EGSs) for several hours. Responses to single stimuli were minimally altered during TTX block of the EGSs. This selective reduction of epileptiform activity could result from general blockade of action potentials in an anatomically distinct group of neurons in the slice. To test this hypothesis, we systematically mapped TTX injection sites in the hippocampal slice, and found that TTX injections that blocked EGSs were nearly always located in or invaded CA2/3 stratum radiatum and/or stratum lacunosum-moleculare. A high degree of recurrent activity in this region contributes to both epileptiform activity and responses to single stimuli; hence our selective inhibition of EGSs suggests a more pharmacologically specific anticonvulsant effect of TTX. Consistent with this hypothesis, we found that low concentrations of TTX (5, 10, or 20 nM) in the perfusion medium blocked EGSs without decreasing the amplitude of extracellular responses to single stimuli. Polysynaptic activity and/or antidromic firing may be particularly vulnerable to TTX action on voltage-gated sodium channels, due to their lower the safety factor for action potential propagation. Selective reduction of this activity may disrupt the abnormal neuronal activity underlying EGSs.