Disease-specific, neurosphere-derived cells as models for brain disorders

There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery

Immunoglobulins reactive to carcinoembryonic antigen and their relationship to the antigen in malignant ascitic fluid of ovarian carcinoma

Samples of malignant ascitic fluid from 30 patients with advanced ovarian carcinoma were examined for the presence of IgM antibodies to CEA and PEG‐precipitable proteins binding to I‐CEA. The IgM antibodies to CEA were measured by a solid‐phase radioimmunoassay using ovarian CEA. There was no correlation between the level of IgM antibodies to CEA and that of total IgM in the fluid. In 11 of 30 (37%) samples tested, significant amounts of IgM antibodies to CEA were found. The CEA‐binding proteins were measured by the ability of ascitic fluid to incorporate I‐colonic‐CEA into PEG‐precipitable complexes. In 9 of 39 (30%) samples, the precipitation was significant. There was no association between antibodies to the ABO and Lewis blood group factors and these antibodies to CEA. An inverse relationship was observed between the level of CEA and that of CEA‐binding proteins shown by the two assays. When I‐CEA was incubated with these “positive” samples, a high molecular weight fraction was demonstrated by chromatography. By contrast, in the “negative” samples, there was no incorporation of I‐CEA. These findings would indicate the presence of CEA‐reactive proteins possibly existing as immune‐complex‐like material in ascitic fluid of some patients

Enhanced somatosensory information decreases postural sway in older people

The somatosensory system plays an important role in balance control and age-related declines in somatosensory function have been implicated in falls incidence. Different types of insole devices have been developed to enhance somatosensory information and improve postural stability. However, they are often too complex and expensive to integrate into daily life and textured insole surfaces may provide an inexpensive and accessible means to enhance somatosensory input. This study investigated the effects of textured insole surfaces on postural sway in ten younger and seven older participants performing standing balance tests on a force plate under three insole surface conditions: (1) barefoot; (2) with hard; and (3), soft textured insole surfaces. With each insole surface, participants were tested under two vision conditions (eyes open, closed) on two standing surfaces (firm, foam). Four 30s trials were collected for different combinations of insole surface, standing surface and vision. Centre of pressure measurements included the range and standard deviation of anterior-posterior and medial-lateral displacement, path length and the 90% confidence elliptical area. Results revealed a significant Group*Surface*Insole interaction for five of the dependent variables. Compared to younger individuals, postural sway was greater in older people on both standing surfaces in the barefoot condition. However, both textured insole surfaces reduced postural sway for the older group especially in the eyes closed condition on a foam surface. These findings suggest that textured insole surfaces can reduce postural sway in older people, particularly during more challenging balance tasks. Textured insole surfaces may afford a low-cost means of decreasing postural sway, providing an important intervention in falls prevention

Supplementary Material for: Globus Pallidus Internus Deep Brain Stimulation as Rescue Therapy for Refractory Dyskinesias following Effective Subthalamic Nucleus Stimulation

<b><i>Background:</i></b> Deep brain stimulation (DBS) at the subthalamic nucleus (STN) or globus pallidus internus (GPi) can effectively treat the motor symptoms of Parkinson's disease, but dual implantation is rare. We report the first cases of additional GPi stimulation as rescue therapy for disabling dyskinesias following successful STN stimulation. <b><i>Methods:</i></b> Two patients, initially treated with bilateral STN DBS, underwent subsequent bilateral GPi DBS after the development of refractory dyskinesias within 1 and 6 years of STN surgery. Patients were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) before and after surgeries for STN and GPi DBS. <b><i>Results:</i></b> GPi DBS effectively suppressed dyskinesias in these patients and improved their quality of life, as demonstrated by their videos and UPDRS scores. <b><i>Conclusions:</i></b> Additional bilateral GPi DBS may be considered in the rare instance of patients who develop refractory dyskinesias early or late after bilateral STN DBS

Variability, regularity and coupling measures distinguish PD tremor from voluntary 5 Hz tremor

A characteristic of Parkinson's disease (PD) is the development of tremor within the 4-6. Hz range. One method used to better understand pathological tremor is to compare the responses to tremor-type actions generated intentionally in healthy adults. This study was designed to investigate the similarities and differences between voluntarily generated 4-6. Hz tremor and PD tremor in regards to their amplitude, frequency and coupling characteristics. Tremor responses for 8 PD individuals (on- and off-medication) and 12 healthy adults were assessed under postural and resting conditions. Results showed that the voluntary and PD tremor were essentially identical with regards to the amplitude and peak frequency. However, differences between the groups were found for the variability (SD of peak frequency, proportional power) and regularity (Approximate Entropy, ApEn) of the tremor signal. Additionally, coherence analysis revealed strong inter-limb coupling during voluntary conditions while no bilateral coupling was seen for the PD persons. Overall, healthy participants were able to produce a 5. Hz tremulous motion indistinguishable to that of PD patients in terms of peak frequency and amplitude. However, differences in the structure of variability and level of inter-limb coupling were found for the tremor responses of the PD and healthy adults. These differences were preserved irrespective of the medication state of the PD persons. The results illustrate the importance of assessing the pattern of signal structure/variability to discriminate between different tremor forms, especially where no differences emerge in standard measures of mean amplitude as traditionally defined

Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted. © 2016 Elsevier Inc

Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study

10.1016/j.neurobiolaging.2016.09.022Neurobiology of Aging49217.e1-217.e4NEAG

Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson&apos;s disease: analysis of a large multicenter study

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson&apos;s disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson&apos;s Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted. © 2016 Elsevier Inc