From iPS Cells to Rodents and Nonhuman Primates: Filling Gaps in Modeling Parkinson's Disease

Parkinson's disease (PD) is primarily known as a movement disorder because of typical clinical manifestations associated with the loss of dopaminergic neurons in the substantia nigra. However, it is now widely recognized that PD is a much more complex condition, with multiple and severe nonmotor features implicating additional brain areas and organs in the disease process. Pathologically, typical forms of PD are characterized by the accumulation of α-synuclein-rich protein inclusions known as Lewy bodies and Lewy neurites, although other types of protein inclusions are also often present in the brain. Familial forms of PD have provided a wealth of information about molecular pathways leading to neurodegeneration, but only to add to the complexity of the problem and uncover new knowledge gaps. Therefore, modeling PD in the laboratory has become increasingly challenging. Here, we discuss knowledge gaps and challenges in the use of laboratory models for the study of a disease that is clinically heterogeneous and multifactorial. We propose that the combined use of patient-derived cells and animal models, along with current technological tools, will not only expand our molecular and pathophysiological understanding of PD, but also assist in the identification of therapeutic strategies targeting relevant pathogenic pathways. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.     

MSA-C is the predominant clinical phenotype of MSA in Japan: analysis of 142 patients with probable MSA

We investigated the clinical features and mode of disease progression in 142 patients with probable multiple system atrophy (MSA) according to the Consensus Criteria. The subjects included 84 men and 58 women with a mean age at onset of 58.2+/-7.1 years (range: 38-79 years). Cerebellar signs were detected in 87.3% of these patients at the time of initial examination, and were found in 95.1% of them at latest follow-up. MSA-C was diagnosed in 83.8% of the patients at their first examination. Parkinsonism was initially detected in 28.9% of the patients, increasing to 51.4% at the latest follow-up. Among all of the subjects, only 16.2% were classified as having MSA-P on initial examination. At the latest follow-up, parkinsonian features had become predominant over cerebellar features in 24.6% of the 65 patients with MSA-C who were followed for more than 3 years. Although parkinsonism usually masked the signs of cerebellar involvement in MSA-C patients, none of the patients with MSA-P at an early stage showed predominance of cerebellar features at the latest follow-up. Parkinsonism is the predominant feature of MSA among Western patients, even at an early stage, but this study showed that cerebellar deficits are the main feature in Japanese patients. This difference of disease manifestations between ethnic groups suggests that genetic factors may influence the clinical phenotype of MSA.     

A partial GDNF depletion leads to earlier age-related deterioration of motor function and tyrosine hydroxylase expression in the substantia nigra

Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for peripheral organs, spinal cord, and midbrain dopamine (DA) neurons. Levels of GDNF deteriorate in the substantia nigra in Parkinson's disease (PD). A heterozygous mouse model was created to assess whether chronic reductions in this neurotrophic factor impact motor function and the nigrostriatal dopamine system during the aging process. Due to the important role GDNF plays in kidney development, kidney function and histology were assessed and were found to be normal in both wild-type (WT) and GDNF+/- mice up to 22 months of age. Further, the animals of both genotypes had similar weights throughout the experiment. Locomotor activity was assessed for male WT and GDNF+/- mice at 4-month intervals from 4 to 20 months of age. Both GDNF+/- and WT mice exhibited an age-related decline in horizontal activity, although this was found 4 months earlier in GDNF+/- mice, at 12 months of age. Comparison of young (8 month old) and aged (20 month old) GDNF+/- and WT mice on an accelerating rotarod apparatus established a deficiency for aged but not young GDNF+/- mice, while aged WT mice performed as well as young WT mice on this task. Finally, both WT and GDNF+/- mice exhibited an age-related decrease in substantia nigra TH immunostaining, which was accelerated in the GDNF+/- mice. These behavioral and histological alterations suggest that GDNF may be an important factor for maintenance of motor coordination and spontaneous activity as well as DA neuronal function during aging, and further suggest that GDNF+/- mice may serve as a model for neuroprotective or rescue studies.     

The difference in putamen volume between MSA and PD: Evidence from a meta-analysis

BackgroundThe accurate and non-invasive tool for differential diagnosis between multiple system atrophy (MSA) and Parkinson's disease (PD) is needed at the early stage of disease for clinical trials of disease modifying therapy. PET is helpful, but the availability is limited. MRI is considered to be more available and potential method instead of PET. We aimed to investigate the effect of MSA and PD on putamen volume using a meta-analysis approach.MethodsA computer literature search yielded 6 eligible studies. Putamen volume was expressed as the standardized mean difference between MSA and PD patients. Moreover, subgroup analyses planed to be performed in order to identify factors which contributed to heterogeneity if included studies were not homogeneous. The proportion of variation due to heterogeneity was computed and expressed as I².ResultsSix studies, comprising a sample size of 84 MSA and 180 PD, were included in this meta-analysis. The overall effect indicated that putamen volume in MSA was significantly more reduced than that in PD with heterogeneous studies (P = 0.0004, 6 studies, n = 264, I² = 87%). A subgroup analysis revealed that the category of “Hoehn–Yahr stage of PD” showed a significant subgroup difference with a significant subgroup summary effect (subgroup difference: P = 0.003).ConclusionsOur findings based on group-level analysis suggested that volumetry of the putamen could be useful for differential diagnosis between MSA and PD at the early stage of disease, and also help to enroll more accurate disease group for disease modifying study in future.     

Coexistence of PSP and MSA: a case report and review of the literature

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy characterized by Parkinsonism, vertical gaze palsy, and early falls. The neuropathology is characterized by neurofibrillary tangles, tufted astrocytes, and coiled bodies, but some brains show other pathologic processes. To investigate the frequency of α-synuclein pathology in PSP with immunohistochemistry and to report the clinical and pathological features of a case of PSP with concomitant Multiple system atrophy (MSA) (PSP/MSA), 290 cases of PSP were screened for α-synuclein pathology with immunohistochemistry. Double-labeling immunohistochemistry was performed on a case of PSP/MSA. Among the PSP cases screened for α-synuclein pathology, a single case of PSP/MSA was detected. The patient was an 86-year-old woman with clinical features consistent with PSP. She had no documented dysautonomia or cerebellar signs, and imaging studies were not diagnostic of MSA. Pathological examination showed τ-immunoreactive neuronal and glial lesions consistent with PSP as well as α-synuclein immunoreactive glial cytoplasmic inclusions diagnostic of MSA. Double-immunolabeling studies showed no co-localization of α-synuclein and τ in most neuronal and glial lesions. Based upon the findings in this case, the neuropathologic changes of PSP and MSA are distinct and independent processes, but they can occasionally coexist.     

Applying bioinformatics to proteomics: Is machine learning the answer to biomarker discovery for PD and MSA?

Bioinformatics tools are increasingly being applied to proteomic data to facilitate the identification of biomarkers and classification of patients. In the June, 2012 issue, Ishigami et al. used principal component analysis (PCA) to extract features and support vector machine (SVM) to differentiate and classify cerebrospinal fluid (CSF) samples from two small cohorts of patients diagnosed with either Parkinson's disease (PD) or multiple system atrophy (MSA) based on differences in the patterns of peaks generated with matrix‐assisted desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS). PCA accurately segregated patients with PD and MSA from controls when the cohorts were combined, but did not perform well when segregating PD from MSA. On the other hand, SVM, a machine learning classification model, correctly classified the samples from patients with early PD or MSA, and the peak at m/z 6250 was identified as a strong contributor to the ability of SVM to distinguish the proteomic profiles of either cohort when trained on one cohort. This study, while preliminary, provides promising results for the application of bioinformatics tools to proteomic data, an approach that may eventually facilitate the ability of clinicians to differentiate and diagnose closely related parkinsonian disorders. © 2012 Movement Disorder Society     

How to diagnose MSA early: the role of magnetic resonance imaging

Summary. The clinical differentiation between Parkinson’s disease (PD) and multiple system atrophy (MSA) remains a challenge for each neurologist. The use of different magnetic resonance imaging (MRI) techniques including conventional MRI, proton magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), magnetization transfer imaging (MTI) and MR volumetry (MRV) offer the potential for objective criteria in the differential diagnosis of neurodegenerative parkinsonism. The aim of this article is to review the role of different MRI techniques in the differential diagnosis of PD and MSA.     

How to diagnose MSA early: the role of sphincter EMG

Summary. Multiple system atrophy (MSA) is a degenerative disease manifesting a combination of parkinsonism, cerebellar, pyramidal, and autonomic (including urinary, sexual and anorectal) dysfunction. It is pathomorphologically defined, but lacks a definitive clinical diagnostic test. In patients with probable MSA, abnormal sphincter EMG, as compared to control subjects, has been found in the majority of patients in all the different forms of the disease in most studies, including patients who, as yet, have no urological or anorectal problems. Patients with Parkinson’s disease (PD) as a rule do not show marked sphincter EMG abnormalities in the first five years of the disease. Thus, abnormal spontaneous activity or marked motor unit potential changes in sphincter muscles are helpful in distinguishing MSA from PD in the first five years after the onset of symptoms and signs, and from pure autonomic failure, as well as from cerebellar ataxias, if other causes for sphincter denervation have been ruled out. EMG does not distinguish MSA from progressive supranuclear palsy. How early in the course of MSA these abnormalities become significant enough to support diagnosis remains to be established by prospective studies.     

Decreased striatal dopamine D2 receptor binding in amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA): D2 receptor down-regulation versus striatal cell degeneration

Recently, decreased striatal dopamine D2-receptor binding was demonstrated in vivo in amyotrophic lateral sclerosis (ALS). To further elucidate the pathogenetic mechanism underlying this D2-receptor deficit, a multi-level comparison was made between 30 sporadic ALS subjects and 24 patients with multiple system atrophy (MSA), a disorder clinically characterized by bradykinesia, neuroradiologically by severe D2-receptor loss, and neuropathologically by degenerating striatal cells. The extent of D2-deficit in ALS and MSA were within the same range, but extrapyramidal signs and symptoms were virtually absent in our ALS patients. Striatal cell loss in general or competitive D2-receptor occupancy could be considered unlikely in ALS. The striatum receives massive glutamatergic input and the pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. As other mechanisms (cell loss, receptor occupancy) could be ruled out, and as animal studies suggest that (excess of) glutamate decreases striatal D2-receptor synthesis, the striatal D2-receptor deficit in ALS is most likely to be caused by a receptor down-regulation.     

A decade from discovery to therapy: Lingo-1, the dark horse in neurological and psychiatric disorders

Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) is a potent negative regulator of neuron and oligodendrocyte survival, neurite extension, axon regeneration, oligodendrocyte differentiation, axonal myelination and functional recovery; all processes highly implicated in numerous brain-related functions. Although playing a major role in developmental brain functions, the potential application of Lingo-1 as a therapeutic target for the treatment of neurological disorders has so far been under-estimated. A number of preclinical studies have shown that various methods of antagonizing Lingo-1 results in neuronal and oligodendroglial survival, axonal growth and remyelination; however to date literature has only detailed applications of Lingo-1 targeted therapeutics with a focus primarily on myelination disorders such as multiple sclerosis and spinal cord injury; omitting important information regarding Lingo-1 signaling co-factors. Here, we provide for the first time a complete and thorough review of the implications of Lingo-1 signaling in a wide range of neurological and psychiatric disorders, and critically examine its potential as a novel therapeutic target for these disorders.     

三重刺激技术定量评价多系统萎缩患者重复经颅磁刺激治疗效果二例分析

研究背景既往研究显示,初级运动皮质予重复经颅磁刺激可以改善皮质脊髓束损害。本研究采用三重刺激技术定量评价2例以帕金森综合征为主要表现的多系统萎缩(MSA-P)患者重复经颅磁刺激前后皮质脊髓束功能变化,探讨重复经颅磁刺激对皮质脊髓束损害的改善作用。方法 2例MSA-P型患者(1例为62岁男性,1例为44岁女性),病程1年,均接受重复经颅磁刺激,采用小指展肌三重刺激技术波幅比和统一多系统萎缩评价量表第二部分(UMSARSⅡ)评价治疗前后皮质脊髓束功能和运动功能。结果 2例MSA-P型患者治疗前小指展肌三重刺激技术波幅比为28.30%和69.10%,UMSARSⅡ评分22和20分;治疗后即刻小指展肌三重刺激技术波幅比为58.40%和71.70%,UMSARSⅡ评分16和12分,其中例1随访至重复经颅磁刺激后2个月,治疗后1和2个月小指展肌三重刺激技术波幅比分别为90.70%和50.70%,UMSARSⅡ评分17和23分。结论采用三重刺激技术可以定量评价重复经颅磁刺激对MSA-P型患者皮质脊髓束损害的改善作用。     

The contribution of optic flow to freezing of gait in left- and right-PD: Different mechanisms for a common phenomenon?

It has been recently hypothesized that impaired processing of optic flow may be related to FOG, especially in PD patients with left-side symptomatology (LPD). The current preliminary study examined the frequency of FOG episodes in LPD and RPD while the availability of optic flow was manipulated during gait. Twelve patients (6 FOG-L, 6 FOG-R) completed walking trials in two conditions (optic flow or no optic flow). Results revealed that FOG frequency was similar between groups when optic flow was not available, however, optic flow provided by walking toward an illuminated doorframe, lead to a three-fold increase in FOG episodes in only the LPD (compared to RPD). These findings suggest that LPD might have deficits in perceiving or processing optic flow when passing through doorways. Thus, it is important to consider how sensory processing mechanisms may contribute to severe gait disturbances such as FOG.     

Autonomic Dysfunction in Sleep Disorders: From Neurobiological Basis to Potential Therapeutic Approaches

Sleep disorder has been portrayed as merely a common dissatisfaction with sleep quality and quantity. However, sleep disorder is actually a medical condition characterized by inconsistent sleep patterns that interfere with emotional dynamics, cognitive functioning, and even physical performance. This is consistent with sleep abnormalities being more common in patients with autonomic dysfunction than in the general population. The autonomic nervous system coordinates various visceral functions ranging from respiration to neuroendocrine secretion in order to maintain homeostasis of the body. Because the cell population and efferent signals involved in autonomic regulation are spatially adjacent to those that regulate the sleep-wake system, sleep architecture and autonomic coordination exert effects on each other, suggesting the presence of a bidirectional relationship in addition to shared pathology. The primary goal of this review is to highlight the bidirectional and shared relationship between sleep and autonomic regulation. It also introduces the effects of autonomic dysfunction on insomnia, breathing disorders, central disorders of hypersomnolence, parasomnias, and movement disorders. This information will assist clinicians in determining how neuromodulation can have the greatest therapeutic effects in patients with sleep disorders.     

Pharmacological aspects of antiseizure medications: From basic mechanisms to clinical considerations of drug interactions and use of therapeutic drug monitoring

Antiseizure medications (ASMs) are the cornerstone of treatment for patients with epilepsy. Several new ASMs have recently been introduced to the market, making it possible to better tailor the treatment of epilepsy, as well as other indications (psychiatry and pain disorders). For this group of drugs there are numerous pharmacological challenges, and updated knowledge on their pharmacodynamic and pharmacokinetic properties is, therefore, crucial for an optimal treatment outcome. This review focuses on educational approaches to the following learning outcomes as described by the International League Against Epilepsy (ILAE): To demonstrate knowledge of pharmacokinetics and pharmacodynamics, drug interactions with ASMs and with concomitant medications, and appropriate monitoring of ASM serum levels (therapeutic drug monitoring, TDM). Basic principles in pharmacology, pharmacokinetic variability, and clinically relevant approaches to manage drug interactions are discussed. Furthermore, recent improvements in analytical technology and sampling are described. Future directions point to the combined implementation of TDM with genetic panels for proper diagnosis, pharmacogenetic tests where relevant, and the use of biochemical markers that will all contribute to personalized treatment. These approaches are clinically relevant for an optimal treatment outcome with ASMs in various patient groups.     

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer’s disease, Parkinson’s disease, Huntington’s chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0381-7) contains supplementary material, which is available to authorized users.     

From antibody to clinical phenotype,the black box of the antiphospholipid syndrome: Pathogenic mechanisms of the antiphospholipid syndrome

The antiphospholipid syndrome (APS) is diagnosed by the combination of vascular thrombosis and/or pregnancy morbidity and the detection of antiphospholipid antibodies (aPLs) in plasma. In the last few years, a great effort has been made to unravel the mechanism by which aPLs cause thrombosis and a vast amount of mechanisms have been proposed. aPLs were proposed to induce a prothrombotic state by influencing the cellular blood compartment, the plasma compartment, the vascular wall and even metabolic pathways beyond the hemostatic system. However, due to the diversity in the mechanisms and the differences in the methodology, the focus of the mechanistical studies in this field seems to be largely diffused. It is hard to imagine that aPLs can exert such a diversity of effects, resulting in either thrombosis and/or pregnancy morbidity and the relationship between aPLs and the clinical manifestations remains to be a mysterious “black box”. In an attempt to get insight in what takes place inside the black box, we have analyzed 126 mechanistical studies on aPLs and discussed differences in the type of antibodies that were used, the involvement of beta2-glycoprotein I (β₂GPI), and the criteria used to diagnose APS patients.