Chi Wang Ip

University Hospital Würzburg · Department of Neurology

Background Dystonia is a neurological movement disorder characterised by abnormal involuntary movements and postures, particularly affecting the head and neck. However, current clinical assessment methods for dystonia rely on simplified rating scales which lack the ability to capture the intricate spatiotemporal features of dystonic phenomena, hind...

In Parkinson's disease (PD), pathomechanisms such as aberrant network dysfunctions can be elucidated by conducting multiscale explorations in animal models. However, the lack of specificity in the existing models limits a restricted targeting of individual network elements and characterization of PD as a "circuitopathy". We therefore developed a ce...

Disturbed motor control is a hallmark of Parkinson's disease (PD). Cortico-striatal synapses play a central role in motor learning and adaption, and brain-derived neurotrophic factor (BDNF) from cortico-striatal afferents modulates their plasticity via TrkB in striatal medium spiny projection neurons (SPNs). We studied the role of dopamine in modul...

Deep brain stimulation (DBS) is a well-established symptomatic treatment for patients with Parkinson’s disease (PD). However, cellular mechanisms are not well understood. To close this knowledge gap, animal experiments are currently indispensable. However, basic research is hampered by the fact that only stationary DBS setups are readily available....

Introduction: Dystonia is a movement disorder of variable etiology and clinical presentation and is accompanied by tremor in about 50% of cases. Monogenic causes in dystonia are rare, but also in the group of non-monogenic dystonias 10-30% of patients report a family history of dystonia. This points to a number of patients currently classified as...

Inhibitors of monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) are major strategies to reduce levodopa degradation and thus to increase and prolong its effect in striatal dopaminergic neurotransmission in Parkinson’s disease patients. While selegiline/rasagiline and tolcapone/entacapone have been available on the market for more...

Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects...

The relationship between genotype and phenotype in DYT-TOR1A dystonia as well as the associated motor circuit alterations are still insufficiently understood. DYT-TOR1A dystonia has a remarkably reduced penetrance of 20-30%, which has led to the second-hit hypothesis emphasizing an important role of extragenetic factors in the symptomatogenesis of...

Background Regulatory CD4 ⁺ CD25 ⁺ FoxP3 ⁺ T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson’s disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create...

The pathogenesis of Parkinson's disease (PD) is closely interwoven with the process of aging. Moreover, increasing evidence from human postmortem studies and from animal models for PD point towards inflammation as an additional factor in disease development. We here assessed the impact of aging and inflammation on dopaminergic neurodegeneration in...

Intracerebral recordings from movement disorders patients undergoing deep brain stimulation have allowed the identification of pathophysiological patterns in oscillatory activity that correlate with symptom severity. Changes in oscillatory synchrony occur within and across brain areas, matching the classification of movement disorders as network di...

Degeneration of the nigrostriatal tract is a neuropathological hallmark of Parkinson’s disease (PD). A differential intraneuronal vulnerability of dopaminergic neurons within the substantia nigra (SN) has been suggested, starting as an axonopathy followed by neuronal cell loss that is accompanied with motor deficits. To date, there is no therapy av...

Parkinson’s disease (PD) is a progressive and debilitating chronic disease that affects more than six million people worldwide, with rising prevalence. The hallmarks of PD are motor deficits, the spreading of pathological α-synuclein clusters in the central nervous system, and neuroinflammatory processes. PD is treated symptomatically, as no causal...

Introduction: The neuropathology induced by injection of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a commonly used and well characterized animal model of Parkinson's disease (PD). It shows pathophysiological hallmarks of PD such as the loss of dopaminergic neurons from the substantia nigra (SN) as well as neuroinflammati...

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Aside from the known correlation with progressive α-Synuclein (αSyn) clustering, PD is also associated with neuroinflammation. An increased activity of the inflammasome and its main-component NOD-, LRR- and pyrin domain- containing protein 3 (NLRP...

Background: The assessment of eye movements is commonly considered a “window into the brain”. However, sole clinical observation is limited to semiquantitative findings. Recent advances in quantitative oculomotor phenotyping using video-oculography (VOG) promise additional diagnostic and prognostic value. However, methodological complexity and limi...

Introduction: DYT-TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and a reduced penetrance of 30–40%. To analyse whether environmental factors in genetically predisposed DYT-TOR1A patients can act as a potential trigger for the development of a dystonic phenotype, we aimed to induce dystonia-like symptoms in h...

Background: Phenomenological description, diagnosis and assessment of disease development, as well as treatment effects, of movement disorders still heavily relies on clinical assessment using scoring scales. However, these scales are inherently prone to rater biases, thereby negatively affecting their reliability and comparability. Objective: To l...

Introduction: Aberrant beta (13-35 Hz) synchrony within the cortico-basal ganglia circuit has been reported as disease-specific hallmark of human Parkinson's disease (PD). The suppression of pathologically enhanced beta oscillations following subthalamic deep brain stimulation (STN-DBS ) is considered to be a crucial mechanism mediating improved mo...

Introduction: Parkinson's disease (PD) is classically known for its characteristic motor symptoms of bradykinesia, rigidity, and tremor. However, this disease is riddled with an assortment of non-motor manifestations, such as constipation, which is actually one of the first symptoms that patients experience. Investigations in the intestines of PD p...

Introduction: Abnormally enhanced beta (13–35 Hz) activity, recorded in the subthalamic nucleus (STN) of Parkinson’s disease (PD) patients and PD animal models, represents the electrophysiological biomarker of nigrostriatal degeneration. In this study, we investigated the local field potential (LFP) activity in the progressive AAV1/2-A53T-a-synucle...

Introduction: Abnormal postures or movements caused by sustained or intermittent muscle contractions typically characterize the hyperkinetic movement disorder dystonia. DYT-TOR1A dystonia is the most common form of monogenic dystonia and follows an autosomal dominant pattern of inheritance. Although a trinucleotide deletion in the torsinA encoding...

Aim An accumulating body of evidence suggests the involvement of alpha-synuclein (aSyn) specific autoreactive T cells in Parkinson’s disease (PD). Here, we investigate whether novel antigen-specific tolerance-inducing biomolecules, that present peptide antigens on MHC class Ib-related molecules, can inhibit neurodegeneration and prevent PD in vivo....

Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP‐A) is a steroid‐responsive meningoencephalomyelitis, sometimes presenting with atypical clinical signs such as movement disorders or psychiatric and autonomic features. Beyond clinical presentation and imaging, diagnosis relies on detection of GFAP‐antibodies (AB) in CSF. Using quantit...

Gait impairments in Parkinson's disease remain a scientific and therapeutic challenge. The advent of new deep brain stimulation (DBS) devices capable of recording brain activity from chronically implanted electrodes has fostered new studies of gait in freely moving patients. The hope is to identify gait-related neural biomarkers and improve therapy...

Background Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson’s disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic...

Deep Brain Stimulation (DBS) is an efficacious treatment option for an increasing range of brain disorders. To enhance our knowledge about the mechanisms of action of DBS and to probe novel targets, basic research in animal models with DBS is an essential research base. Beyond nonhuman primate, pig, and mouse models, the rat is a widely used animal...

Deep brain stimulation (DBS) is the preferred treatment for therapy-resistant movement disorders such as dystonia and Parkinson's disease (PD), mostly in advanced disease stages. Although DBS is already in clinical use for ~30 years and has improved patients' quality of life dramatically, there is still limited understanding of the underlying mecha...

One of the great mysteries in dystonia pathophysiology is the role of environmental factors in disease onset and development. Progress has been made in defining the genetic components of dystonic syndromes, still the mechanisms behind the discrepant relationship between dystonic genotype and phenotype remain largely unclear. Within this review, the...

Objective Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a steroid-responsive meningoencephalomyelitis, sometimes presenting with atypical clinical signs such as movement disorders or psychiatric and autonomic features. Diagnosis relies on clinical presentation, detection of GFAP autoantibodies in CSF as well as ancillary MRI...

Regional iron accumulation and α‐synuclein (α‐syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to α‐syn, facilitating its aggregation and regulating α‐syn expression, it remains unclear if and how iron also modulates α‐syn spreading. To elucidate t...

Zusammenfassung Hintergrund Obwohl Botulinumtoxin‑A (BoNT-A) von Leitlinien als First-line-Therapie der fokalen zervikalen Dystonie (ZD) empfohlen wird, existieren kaum Langzeitdaten zu den Behandlungsmodalitäten in der klinischen Routine. Fragestellung Die vorliegende Subgruppenanalyse untersuchte Patientenzufriedenheit und Symptomkontrolle unte...

TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify centr...

Zusammenfassung Seit der Erstbeschreibung einer monogenetischen Ursache der Parkinson-Erkrankung sind mehr als 20 Jahre vergangen. Trotz der Fortschritte der molekulargenetischen Diagnostik wird diese immer noch sehr selten durchgeführt. Genetische Untersuchungen bei Patienten mit Parkinson-Syndromen werden allerdings zukünftig einen großen Stellen...

The disease-causing A53T mutation of α-synuclein (PARK1) was adopted to generate and study pathophysiologic effects in several animal models shortly after its discovery. It is used to create transgenic parkinsonian animal models in Drosophila and mice, and it is also possible to deliver A53T α-synuclein via viral vectors directly into a desired bra...

Background Programming deep brain stimulation in dystonia is difficult because of the delayed benefits and absence of evidence-based guidelines. Therefore, we evaluated the efficacy of a programming algorithm applied in a double-blind, sham-controlled multicenter study of pallidal deep brain stimulation in dystonia. Methods A standardized monopola...

Rapid-onset dystonia-parkinsonism (RDP) is a rare form of hereditary dystonia caused by loss-of-function mutations of the Na+/K+-ATPase α3 isoform (ATP1α3). An acute onset of generalized dystonia and parkinsonism after exposure to stress and an incomplete disease penetrance is described in RDP, thereby suggesting a gene-environmental interaction in...

Delirium is an acute and fluctuating disturbance of attention and awareness. Pre-existing cognitive disturbances or dementia are the most significant risk factors for developing delirium and precipitating factors such as drug treatment, infections, trauma, or surgery may trigger delirium. Patients with Parkinson’s disease (PD) are at an increased r...

The use of viral vector-mediated α-synuclein-overexpressing rodent models for Parkinson’s disease has become increasingly accepted to study associated pathology and to use as a platform for therapeutic efficacy testing. We here describe methods to generate such models and how to analyze them by behavioral assessments, histological investigations, a...

Zusammenfassung Schmerzen beim idiopathischen Parkinsonsyndrom (IPS) treten bei 40 %–95 % der Patienten auf und beeinträchtigen die Lebensqualität, sind jedoch oftmals unterdiagnostiziert und werden nur unsystematisch therapiert. Schmerzätiologie und Schmerzcharakter können sehr vielfältig sein und obwohl die Optimierung der Parkinson-Medikation di...

In pre-clinical Parkinson’s disease research, analysis of the nigrostriatal tract, including quantification of dopaminergic neuron loss within the substantia nigra, is essential. To estimate the total dopaminergic neuron number, unbiased stereology using the optical fractionator method is currently considered the gold standard. Because the theory b...

Objective: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective symptomatic therapy for motor deficits in Parkinson's disease (PD). An additional, disease-modifying effect has been suspected from studies in toxin-based PD animal models, but these models do not reflect the molecular pathology and progressive nature of...

α-Synuclein is a protein implicated in the etiopathogenesis of Parkinson’s disease (PD). AAV1/2-driven overexpression of human mutated A53T-α-synuclein in rat and monkey substantia nigra (SN) induces degeneration of nigral dopaminergic neurons and decreases striatal dopamine and tyrosine hydroxylase (TH). Given certain advantages of the mouse, espe...

Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a st...

Progressive forms of multiple sclerosis lead to chronic disability, substantial decline in quality of life and reduced longevity. It is often suggested that they occur independently of inflammation. Here we investigated disease progression in mouse models carrying PLP1 point mutations previously found in patients displaying clinical features of mul...

Neuroinflammation is a well-known neuropathological feature of Parkinson's disease (PD), but it remains controversial whether it is causal or consequential to neurodegeneration. While the role of microglia in the pathogenesis has been thoroughly investigated in human and different rodent models, data concerning the impact of the adaptive immune sys...

The neuronal ceroid lipofuscinoses are fatal neurodegenerative disorders in which the visual system is affected early in disease progression. A typical accompanying feature is neuroinflammation, the pathogenic impact of which is presently obscure. Here we investigated the role of inflammatory cells in palmitoyl protein thioesterase 1-deficient (Ppt...

Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to signifi...

In transgenic mice overexpressing the major myelin protein of the central nervous system, proteolipid protein, CD8+ T-lymphocytes mediate the primarily genetically caused myelin and axon damage. In the present study, we investigated the cellular and molecular mechanisms underlying this immune-related neural injury. At first, we investigated whether...

Demyelination and death of oligodendrocytes accompanied by transection of neurites and neuronal apoptosis are pathological hallmarks of cortical and subcortical gray matter lesions in demyelinating viral and autoimmune inflammatory CNS disorders. In these disorders, leukocortical lesions, containing the perikarya of most efferent neurons, display p...

It is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well as CNS vulnerability. We challenged this concept experimentally by investigating how genetic alterations that affect myelin (primary oligodendrocyte damag...

Material and Methods S1 (0.03 MB DOC)

Exclusion of differences in the peripheral immune systems of wt, PD-1-/-, PLPtg and PLPtg/PD-1-/- double mutants. Peritoneal macrophages were incubated with fluorescent latex beads and the percentage of macrophages which ingested beads was found similar in all genotypes (A). Differences in the apoptosis rate were excluded by flow cytometry of annex...

CDR3 sequences. Sequencing analysis of two clones with identical VβJβ combinations from PLPtg/PD-1-/- mice A and B and of one clone with a different VβJβ combination from mouse A. Note identical TCRVβ and TCRJβ regions surrounding the CDR3 region, which not only differs in aminoacids but also, more importantly, in length, thus indicating recognitio...

Mice hetero- or homozygously deficient for myelin protein zero (P0+/−, P0−/− mice) are models for distinct forms of inherited de- or dysmyelinating neuropathies, respectively. P0+/− mice show a demyelinating neuropathy with a pathogenetic implication of CD8+ T-lymphocytes and macrophages, while P0−/− mice show dysmyelination with axonal loss. It wa...

We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lym...

We have previously shown that mice heterozygously deficient for P0 are characterized by a late onset myelin disorder implicating CD8+ T-lymphocytes and macrophages. We now investigated the impact of the co-inhibitory molecule “programmed death” (PD)-1 (CD279), a CD28-related receptor expressed on activated T- and B-lymphocytes on the pathogenic phe...