The Cerebrospinal Fluid Profile of Cholesterol Metabolites in Parkinson's Disease and Their Association With Disease State and Clinical Features.

Disordered cholesterol metabolism is linked to neurodegeneration. In this study we investigated the profile of cholesterol metabolites found in the cerebrospinal fluid (CSF) of Parkinson's disease (PD) patients. When adjustments were made for confounding variables of age and sex, 7α,(25R)26-dihydroxycholesterol and a second oxysterol 7α,x,y-trihydroxycholest-4-en-3-one (7α,x,y-triHCO), whose exact structure is unknown, were found to be significantly elevated in PD CSF. The likely location of the additional hydroxy groups on the second oxysterol are on the sterol side-chain. We found that CSF 7α-hydroxycholesterol levels correlated positively with depression in PD patients, while two presumptively identified cholestenoic acids correlated negatively with depression.

Cerebrospinal Fluid Cytokines and Neurodegeneration-Associated Proteins in Parkinson's Disease.

INTRODUCTION: Immune markers are altered in Parkinson's disease (PD), but relationships between cerebrospinal fluid (CSF) and plasma cytokines and associations with neurodegeneration-associated proteins remain unclear. METHODS: CSF and plasma samples and demographic/clinical measures were obtained from 35 PD patients. CSF samples were analyzed for cytokines (together with plasma) and for α-synuclein, amyloid ß(1-42) peptide, total tau, and phospho(Thr231)-tau. RESULTS: There were no CSF-plasma cytokine correlations. Interleukin (IL)-8 was higher and interferon-γ, IL-10, and tumor necrosis factor-α were lower in CSF versus plasma. In CSF, total tau correlated positively with IL-8 and IL-1ß, whereas α-synuclein correlated positively with amyloid ß(1-42) and negatively with semantic fluency (a known marker of PD dementia risk). DISCUSSION: CSF and peripheral cytokine profiles in PD are not closely related. Associations between CSF IL-8 and IL-1ß and tau suggest that CSF inflammatory changes may relate to tau pathology within PD. CSF α-synuclein/amyloid ß may reflect the risk of developing PD dementia. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Determinants of delayed diagnosis in Parkinson's disease.

The early and accurate diagnosis of Parkinson's disease (PD) is the first step towards optimal patient management. The aim of this study was to investigate the major determinants of delayed diagnosis in PD. We recruited a population-representative cohort of 239 newly-diagnosed PD patients who underwent clinical and neuropsychological evaluation. Non-parametric methods were used to define the factors associated with diagnostic delay. The median time from motor symptom onset to primary care physician (PCP) presentation was considerably longer than the time from PCP presentation to PD diagnosis (11 vs. 1 months). Male sex and presenting motor phenotype were independently associated with delayed PCP presentation on Cox regression analysis. Patients presenting with gait disturbance experienced the longest delay, whilst those presenting with tremor had the shortest. In summary, male sex and presenting motor phenotype are key determinants of delayed diagnosis in PD.

Brief report: female-to-male transsexual people and autistic traits.

The 'extreme male brain' theory suggests females with Autism Spectrum Conditions are hyper-masculinized in certain aspects of behavior. We predicted that females with Gender Identity Disorder (who are masculinized) would have elevated Autism Spectrum Quotient (AQ) scores. AQ scores from five groups were compared: (1) n = 61 transmen (female-to-male transsexual people); (2) n = 198 transwomen (male-to-female transsexual people); (3) n = 76 typical males; (4) n = 98 typical females; and (5) n = 125 individuals with Asperger Syndrome (AS). Transmen had a higher mean AQ than typical females, typical males and transwomen, but lower than individuals with AS. Transmen have more autistic traits and may have had difficulty socializing with female peers and thus found it easier to identify with male peer groups.

Stem cells and regenerative therapies for Parkinson's disease.

Currently the mainstay of Parkinson's disease (PD) therapy is the pharmacological replacement of the loss of the dopaminergic nigrostriatal pathway using drugs such as dopamine agonists and levodopa. Whilst these drugs effectively ameliorate some of the motor features of PD, they do not improve many of the nonmotor features that arise secondary to pathology outside of this system, nor do they slow the progressive neurodegeneration that is a characteristic of the disease. Regenerative therapies for PD seek to fill this therapeutic gap, with cell transplantation being the most explored approach to date. A number of different cell sources have been used in this therapeutic approach, but to date, the most successful has been the use of fetal ventral mesencephalic (VM) tissue that contains within it the developing nigral dopaminergic cells. Cell transplantation for PD was pioneered in the 1980-1990s, with several successful open-label trials of fetal VM transplantation in patients with relatively advanced PD. Whilst these findings were not replicated in two subsequent double-blind sham-surgery controlled trials, there were reasons to explain this outside of the one drawn at the time that these therapies are ineffective. Indeed all these studies have provided evidence that following the transplantation of fetal VM tissue, dopaminergic cells can survive long term, produce dopamine, and bring about clinical improvements in younger patients over many years. The use of fetal tissue, irrespective of its true efficacy, will never become a widely available therapy for PD for a host of practical and ethical reasons, and thus much work has been put in recently to exploring the utility of stem cells as a source of nigral dopaminergic neurons. In this respect, the advent of embryonic stem cell and induced pluripotent cells has heralded a new era in cell therapy for PD, and several groups have now demonstrated that these cells can form dopaminergic neurons which improve functional deficits in animal models of PD. Whilst encouraging, problems with respect to the immunogenicity and tumorigenicity of these cells means that they will need to be used in the clinic cautiously. Other regenerative therapies in PD have been tried over the years and include the use of trophic factors. This has primarily involved glial cell line-derived neurotrophic factor (GDNF) and again has produced mixed clinical effects, and in order to try and resolve this, a new trial of intraputamenal GDNF is now being planned. In addition, a new trial for platelet derived growth factor as a treatment for PD has just completed recruitment, and PYM50028 (Cogane) an oral agent shown in animal models to reduce the effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) lesioning by the induction of growth factors is currently under investigation in a multicentre Phase II trial. Overall, there are a number of promising new regenerative therapies being developed and tested in PD, although the true long-term efficacy of any of these in large numbers of patients is still not known.