Parkinson's disease: autoimmunity and neuroinflammation

Parkinson's disease is a neurodegenerative disease that causes the death of dopaminergic neurons in the substantia nigra. The resulting dopamine deficiency in the basal ganglia leads to a movement disorder that is characterized by classical parkinsonian motor symptoms. Parkinson's disease is recognized as the most common neurodegenerative disorder after Alzheimer's disease. PD ethiopathogenesis remains to be elucidated and has been connected to genetic, environmental and immunologic conditions. The past decade has provided evidence for a significant role of the immune system in PD pathogenesis, either through inflammation or an autoimmune response. Several autoantibodies directed at antigens associated with PD pathogenesis have been identified in PD patients. This immune activation may be the cause of, rather than a response to, the observed neuronal loss. Parkinsonian motor symptoms include bradykinesia, muscular rigidity and resting tremor. The non-motor features include olfactory dysfunction, cognitive impairment, psychiatric symptoms and autonomic dysfunction. Microscopically, the specific degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, which are brain deposits containing a substantial amount of α-synuclein, have been recognized. The progression of Parkinson's disease is characterized by a worsening of motor features; however, as the disease progresses, there is an emergence of complications related to long-term symptomatic treatment. The available therapies for Parkinson's disease only treat the symptoms of the disease. A major goal of Parkinson's disease research is the development of disease-modifying drugs that slow or stop the neurodegenerative process. Drugs that enhance the intracerebral dopamine concentrations or stimulate dopamine receptors remain the mainstay treatment for motor symptoms. Immunomodulatory therapeutic strategies aiming to attenuate PD neurodegeneration have become an attractive option and warrant further investigation

Optogenetics and deep brain stimulation neurotechnologies

Brain neural network is composed of densely packed, intricately wired neurons whose activity patterns ultimately give rise to every behavior, thought, or emotion that we experience. Over the past decade, a novel neurotechnique, optogenetics that combines light and genetic methods to control or monitor neural activity patterns, has proven to be revolutionary in understanding the functional role of specific neural circuits. We here briefly describe recent advance in optogenetics and compare optogenetics with deep brain stimulation technology that holds the promise for treating many neurological and psychiatric disorders

Electron microscopy analysis of alpha-synuclein and LRRK2 transgenic C. elegans

Thesis (M.A.)--Boston UniversityMutations in alpha-synuclein and leucine-rich repeat kinase 2 (LRRK2) have been implicated in the cause of Parkinson’s disease (PD). These two proteins have been the targets of a great deal of recent research that has transformed our understanding of this disorder. Recent research using C. elegans as a model species has shown that alpha- synuclein expression and the LRRK2-G2019S mutation potentiate neurodegeneration similar to that seen in cases PD. Further exploration revealed that defects in autophagy of dopaminergic neurons may be the cause for the observed pathology. In the current study, the confirmation of autophagy as a possible cause of pathology due to the expression of alpha-synuclein and the LRRK2-G2019S mutation is completed through the use of electron microscopy. We observed that large vacuoles had formed in the cephalic dopaminergic neurons of alpha-synuclein + LRRK2 transgenic samples not seen in wild-type samples. Further, large morphological changes in the nerve ring area of the transgenic nematodes were also observed that may implicate that alpha- synuclein expression in conjunction with the LRRK2-G2019S mutation may have a widespread effect on many neurons that was not previously expected

Utility of the new Movement Disorder Society clinical diagnostic criteria for Parkinson's disease applied retrospectively in a large cohort study of recent onset cases

Objective: To examine the utility of the new Movement Disorder Society (MDS) diagnostic criteria in a large cohort of Parkinson's disease (PD) patients. Methods: Recently diagnosed (<3.5 years) PD cases fulfilling United Kingdom (UK) brain bank criteria in Tracking Parkinson's, a UK multicenter prospective natural history study were assessed by retrospective application of the MDS criteria. Results: In 2000 cases, 1835 (91.7%) met MDS criteria for PD, either clinically established (n = 1261, 63.1%) or clinically probable (n = 574, 28.7%), leaving 165 (8.3%) not fulfilling criteria. Clinically established cases were significantly more likely to have limb rest tremor (89.3%), a good l-dopa response (79.5%), and olfactory loss (71.1%), than clinically probable cases (60.6%, 44.4%, and 34.5% respectively), but differences between probable PD and ‘not PD’ cases were less evident. In cases not fulfilling criteria, the mean MDS UPDRS3 score (25.1, SD 13.2) was significantly higher than in probable PD (22.3, SD 12.7, p = 0.016) but not established PD (22.9, SD 12.0, p = 0.066). The l-dopa equivalent daily dose of 341 mg (SD 261) in non-PD cases was significantly higher than in probable PD (250 mg, SD 214, p < 0.001) and established PD (308 mg, SD 199, p = 0.025). After 30 months' follow-up, 89.5% of clinically established cases at baseline remained as PD (established/probable), and 86.9% of those categorized as clinically probable at baseline remained as PD (established/probable). Cases not fulfilling PD criteria had more severe parkinsonism, in particular relating to postural instability, gait problems, and cognitive impairment. Conclusion: Over 90% of cases clinically diagnosed as early PD fulfilled the MDS criteria for PD. Those not fulfilling criteria may have an atypical parkinsonian disorder or secondary parkinsonism that is not correctly identified by the UK Brain Bank criteria, but possibly by the new criteria

Motor symptoms in Parkinson's disease: A unified framework

Parkinson’s disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (akinesia and bradykinesia, tremor and rigidity), PD patients show additional motor deficits, including: gait disturbance, impaired handwriting, grip force and speech deficits, among others. Some of these motor symptoms (e.g., deficits of gait, speech, and handwriting) have similar clinical profiles, neural substrates, and respond similarly to dopaminergic medication and deep brain stimulation (DBS). Here, we provide an extensive review of the clinical characteristics and neural substrates of each of these motor symptoms, to highlight precisely how PD and its medical and surgical treatments impact motor symptoms. In conclusion, we offer a unified framework for understanding the range of motor symptoms in PD. We argue that various motor symptoms in PD reflect dysfunction of neural structures responsible for action selection, motor sequencing, and coordination and execution of movement

Subthalamic deep brain stimulation sweet spots and hyperdirect cortical connectivity in Parkinson’s disease

Objectives Firstly, to identify subthalamic region stimulation clusters that predict maximum improvement in rigidity, bradykinesia and tremor, or emergence of side-effects; and secondly, to map-out the cortical fingerprint, mediated by the hyperdirect pathways which predict maximum efficacy. Methods High angular resolution diffusion imaging in twenty patients with advanced Parkinson’s disease was acquired prior to bilateral subthalamic nucleus deep brain stimulation. All contacts were screened one-year from surgery for efficacy and side-effects at different amplitudes. Voxel-based statistical analysis of volumes of tissue activated models was used to identify significant treatment clusters. Probabilistic tractography was employed to identify cortical connectivity patterns associated with treatment efficacy. Results All patients responded well to treatment (46% mean improvement off medication UPDRS-III [p<0.0001]) without significant adverse events. Cluster corresponding to maximum improvement in tremor was in the posterior, superior and lateral portion of the nucleus. Clusters corresponding to improvement in bradykinesia and rigidity were nearer the superior border in a further medial and posterior location. The rigidity cluster extended beyond the superior border to the area of the zona incerta and Forel-H2 field. When the clusters where averaged, the coordinates of the area with maximum overall efficacy was X=-10(-9.5), Y=-13(-1) and Z=-7(-3) in MNI(AC-PC) space. Cortical connectivity to primary motor area was predictive of higher improvement in tremor; whilst that to supplementary motor area was predictive of improvement in bradykinesia and rigidity; and connectivity to prefrontal cortex was predictive of improvement in rigidity. Interpretation These findings support the presence of overlapping stimulation sites within the subthalamic nucleus and its superior border, with different cortical connectivity patterns, associated with maximum improvement in tremor, rigidity and bradykinesia

Objective evaluation of Parkinson's disease bradykinesia

Bradykinesia is the fundamental motor feature of Parkinson’s disease - obligatory for diagnosis and central to monitoring. It is a complex clinicalsign that describes movements with slow speed, small amplitude, irregular rhythm, brief pauses and progressive decrements. Clinical ascertainment of the presence and severity of bradykinesia relies on subjective interpretation of these components, with considerable variability amongst clinicians, and this may contribute to diagnostic error and inaccurate monitoring in Parkinson’s disease. The primary aim of this thesis was to assess whether a novel non-invasive device could objectively measure bradykinesia and predict diagnostic classification of movement data from Parkinson’s disease patients and healthy controls. The second aim was to evaluate how objective measures of bradykinesia correlate with clinical measures of bradykinesia severity. The third aim was to investigate the characteristic kinematic features of bradykinesia. Forty-nine patients with Parkinson’s disease and 41 healthy controls were recruited in Leeds. They performed a repetitive finger-tapping task for 30 seconds whilst wearing small electromagnetic tracking sensors on their finger and thumb. Movement data was analysed using two different methods - statistical measures of the separable components of bradykinesia and a computer science technique called evolutionary algorithms. Validation data collected independently from 13 patients and nine healthy controls in San Francisco was used to assess whether the results generalised. The evolutionary algorithm technique was slightly superior at classifying the movement data into the correct diagnostic groups, especially for the mildest clinical grades of bradykinesia, and they generalised to the independent group data. The objective measures of finger tapping correlated well with clinical grades of bradykinesia severity. Detailed analysis of the data suggests that a defining feature of Parkinson’s disease bradykinesia called the sequence effect may be a physiological rather than a pathological phenomenon. The results inform the development of a device that may support clinical diagnosis and monitoring of Parkinson’s disease and also be used to investigate bradykinesia

Bradykinesia models of Parkinson’s disease

This entry describes a plethora of experimental observations from PD bradykinesia in humans and animals ranging across neuronal, electromyographic and behavioral levels and discusses related theoretical and computational models developed to reproduce and explain these findings. Some computational models of bradykinesia have focused entirely on the effects of dopamine depletion in the basal ganglio-thalamo-cortical relations, whereas others emphasize dopamine depletion in cortico-spino-muscular interactions. Future models will have to produce a more comprehensive and detailed neural model of basal ganglia-thalamo-cortico-spino-muscular interactions, in order to study more systematically the effects of dopamine depletion in these nuclei and integrate into a ‘unified theory’ all the known neurophysiological, EMG and behavioral observations associated with parkinsonism

Motor symptoms of parkinson’s disease -a review literature

Parkinson disease is very common in the world, ranking second to Alzheimers disease in terms of degenerative neurological disorders. The disease since 1817 has had so many researchers looking into it, bringing out symptoms, possible treatment options, causes of the disorder to mention but a few. There are a number of studies that have looked into the symptoms of the disorder, especially the non-motor symptoms of the disorder. This study looks into the motor symptoms associated with the disease. It brought out the causes, which the study from the literature review conducted asserted that there is no known cause for it, however, about 60 to 80 percent of persons with PD, have a degenerating number of dopamine, as such, this can be postulated to be the cause. The study also affirmed that there is no known treatment for the symptoms, doctors and medical practitioners would therefore have to try different forms of treatment till the right one for the patient is arrived at