The Current Status of Neural Grafting in the Treatment of Huntington’s Disease. A Review

Huntington’s disease (HD) is a devastating, fatal, autosomal dominant condition in which the abnormal gene codes for a mutant form of huntingtin that causes widespread neuronal dysfunction and death. This leads to a clinical presentation, typically in midlife, with a combination of motor, psychiatric, cognitive, metabolic, and sleep abnormalities, for which there are some effective symptomatic therapies that can produce some transient benefits. The disease, though, runs a progressive course over a 20-year period ultimately leading to death, and there are currently no proven disease modifying therapies. However whilst the neuronal dysfunction and loss affects much of the central nervous system, the striatum is affected early on in the disease and is one of the areas most affected by the pathogenic process. As a result the prospect of treating HD using neural transplants of striatal tissue has been explored and to date the clinical data is inconclusive. In this review we discuss the rationale for treating HD using this approach, before discussing the clinical trial data and what we have learnt to date using this therapeutic strategy

Cell replacement therapy for Parkinson's disease

AbstractParkinson's disease (PD) is a progressive neurodegenerative disorder in which the degeneration of dopaminergic neurons projecting from the substantia nigra to the striatum is a key pathological feature of the disease. Although pharmacological dopamine replacement is generally very effective in early disease, it is only a symptomatic therapy and can have significant side effects with long term use. One of the key strategies in a more restorative approach to PD therapy involves replacement of this degenerating nigro-striatal dopaminergic network with cells and several possible cell sources are being explored. While much experience and some success have been gained with fetal ventral mesencephalic (FVM) tissue transplants, the rapidly advancing stem cell field is providing attractive alternative options which circumvent many of the ethical and practical problems inherent in trials with FVM tissue. Of these embryonic stem cells and induced pluripotent stem cells seem the most promising. However further development and optimisation of the safety and efficacy of the techniques involved in generating and manipulating these, as well as other, cell sources will be essential before any further clinical trials are carried out

Removal mechanisms and efficiencies of selected heavy metals in constructed wetlands

The removal efficiencies and mechanisms of Pb, Cr, Cd and Zn removal were investigated in batch type constructed wetlands comprising water hyacinth (Eichhornia crassipes (Mart.) Solms) using a mass balance analysis. This study was conducted for 15 weeks in four 590 l capacity tanks containing 3.1, 5, 0.2 and 1.1 mg/l of Pb, Cr, Cd and Zn respectively. Removal efficiencies from the wastewaters were in the range of 92.1-99.6%, 31.3-100%, 46.3-94.4% and 25.1-94.8% for Pb, Cr, Cd and Zn, respectively. The results showed that water hyacinth roots play a crucial role in the removal of Pb and Cr by means of precipitation, though phytoremediation was insignificant. However, phytoremediation through rhizofiltration seemed to govern the removal of Cd and Zn. We conclude that constructed wetlands comprising water hyacinth is a promising low cost option for removing the above heavy metals within the ranges investigated

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 β(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-1β, whereas α-synuclein correlated positively with amyloid β(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-1β and tau suggest that CSF inflammatory changes may relate to tau pathology within PD. CSF α-synuclein/amyloid β 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.Funding for this work was provided by the Rosetrees Trust (M369-F1), Addenbrooke’s Charitable Trust (PF15/CWG) and the NIHR Cambridge Biomedical Research Centre Dementia and Neurodegeneration Theme (146281). RSW was supported by a Fellowship from Addenbrooke’s Charitable Trust (RG77199). SFM was supported by the Transeuro EU FP7 grant (242003) and is now an NIHR Academic Clinical Fellow (ACF-2015-23-501). DPB is supported by a Wellcome Trust Clinical Research Career Development Fellowship. RAB is an NIHR Senior Investigator (NF-SI-0616-10011) and is supported by the Wellcome Trust-MRC Cambridge Stem Cell Institute. CHWG holds a RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1) and receives support from the Cambridge Centre for Parkinson-Plus

Monocyte Function in Parkinson's Disease and the Impact of Autologous Serum on Phagocytosis.

Background: Increasing evidence implicates involvement of the innate immune system in the initiation and progression of Parkinson's disease (PD). Monocytes and monocyte-derived cells perform a number of functions, such as phagocytosis, chemotaxis, and cytokine secretion, which may be particularly relevant to PD pathology. The behavior of these cells in early-moderate disease, in conditions more similar to the in-vivo environment has not been fully evaluated. Research Question: Does monocyte function, including phagocytosis, chemotaxis and cytokine secretion, differ in early-moderate PD compared to age and gender-matched controls? Methods: Participants included PD patients (n = 41) with early-moderate stage disease (Hoehn and Yahr ≤2) and age and gender matched controls (n = 41). Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and monocytes were further separated using CD14 magnetic beads. Functional assays, including bead phagocytosis (in standard medium and autologous serum), Boyden chamber trans-well chemotaxis, and cytokine secretion on lipopolysaccharide stimulation were performed. Monocyte surface markers relating to chemotaxis were measured using immunohistochemistry and flow cytometry. Between-group analysis was performed using paired t-tests. Results: An autologous serum environment significantly increased bead phagocytosis compared to standard medium as expected, in both patients and controls. When in autologous serum, PD monocytes demonstrated enhanced phagocytosis compared to control monocytes (p = 0.029). The level of serum-based phagocytosis was influenced by complement inactivation and the origin of the serum. There were no significant differences between PD and controls in terms of standard medium based monocyte migration or cytokine secretion in this cohort. Conclusions: Autologous serum has a significant influence on monocyte phagocytosis and reveals increased phagocytic capacity in early-moderate PD compared to controls. These conditions may better reflect the function of monocytes in-vivo in PD patients than standard medium based phagocytosis assays. Further studies will be required to replicate these results in larger cohorts, including earlier and later stages of disease, and to understand which serum factors are responsible for this observation and the potential mechanistic relevance to PD pathogenesis.Funding for this work was provided by Addenbrooke’s Charitable Trust, the Rosetrees Trust and the NIHR Cambridge Biomedical Research Centre. RSW was supported by a Fellowship from Addenbrooke’s Charitable Trust. DKV is supported by a Junior Research Fellowship from Homerton College, Cambridge. KMS is supported by a Fellowship from the Wellcome Trust. CHWG is supported by a Clinician Scientist Fellowship from the Medical Research Council. RAB is an NIHR Senior Investigator and is supported by the Wellcome Trust-MRC Cambridge Stem Cell Institute

Senescence and Inflammatory Markers for Predicting Clinical Progression in Parkinson's Disease: The ICICLE-PD Study.

BACKGROUND: Cognitive decline is a frequent complication of Parkinson's disease (PD) and the identification of predictive biomarkers for it would help in its management. OBJECTIVE: Our aim was to analyse whether senescence markers (telomere length, p16 and p21) or their change over time could help to better predict cognitive and motor progression of newly diagnosed PD patients. We also compared these senescence markers to previously analysed markers of inflammation for the same purpose. METHODS: This study examined the association of blood-derived markers of cell senescence and inflammation with motor and cognitive function over time in an incident PD cohort (the ICICLE-PD study). Participants (154 newly diagnosed PD patients and 99 controls) underwent physical and cognitive assessments over 36 months of follow up. Mean leukocyte telomere length and the expression of senescence markers p21 and p16 were measured at two time points (baseline and 18 months). Additionally, we selected five inflammatory markers from existing baseline data. RESULTS: We found that PD patients had shorter telomeres at baseline and 18 months compared to age-matched healthy controls which also correlated to dementia at 36 months. Baseline p16 levels were associated with faster rates of motor and cognitive decline over 36 months in PD cases, while a simple inflammatory summary score at baseline best predicted cognitive score over this same time period in PD patients. CONCLUSION: Our study suggests that both inflammatory and senescence markers (p16) are valuable predictors of clinical progression in PD patients.This study was supported by a Newcastle upon Tyne Hospital Trust (Brain Research Unit PD0612) grant to GS. ICICLE-PD is funded by Parkinson’s UK (grant no J-0802, G-1301) and supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre in Ageing and Chronic Disease and the Biomedical Research Unit in Lewy Body Dementia based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University (CM-R) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (146281). This work was also supported by grants from the Academy of Medical Sciences, UK, the Rosetrees Trust, and the Stevenage Biosciences Catalyst. CHWG is supported by a RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1). RAB is an NIHR Senior Investigator (NF-SI-0616-10011) and is supported by the WT/MRC Stem Cell Institute (203151/Z/16/Z

Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson's disease.

The innate immune system is implicated in Parkinson's disease (PD), but peripheral in-vivo clinical evidence of the components and driving mechanisms involved and their relationship with clinical heterogeneity and progression to dementia remain poorly explored. We examined changes in peripheral innate immune-related markers in PD cases (n = 41) stratified according to risk of developing early dementia. 'Higher Risk'(HR) (n = 23) and 'Lower Risk' (LR) (n = 18) groups were defined according to neuropsychological predictors and MAPT H1/H2 genotype, and compared to age, gender and genotype-matched controls. Monocyte subsets and expression of key surface markers were measured using flow cytometry. Serum markers including alpha-synuclein, inflammasome-related caspase-1 and bacterial translocation-related endotoxin were measured using quantitative immuno-based assays. Specific markers were further investigated using monocyte assays and validated in plasma samples from a larger incident PD cohort (n = 95). We found that classical monocyte frequency was elevated in PD cases compared to controls, driven predominantly by the HR group, in whom Toll-Like Receptor (TLR)4+ monocytes and monocyte Triggering Receptor Expressed on Myeloid cells-2 (TREM2) expression were also increased. Monocyte Human Leukocyte Antigen (HLA)-DR expression correlated with clinical variables, with lower levels associated with worse cognitive/motor performance. Notably, monocyte changes were accompanied by elevated serum bacterial endotoxin, again predominantly in the HR group. Serum alpha-synuclein and inflammasome-related caspase-1 were decreased in PD cases compared to controls regardless of group, with decreased monocyte alpha-synuclein secretion in HR cases. Further, alpha-synuclein and caspase-1 correlated positively in serum and monocyte lysates, and in plasma from the larger cohort, though no associations were seen with baseline or 36-month longitudinal clinical data. Principal Components Analysis of all monocyte and significant serum markers indicated 3 major components. Component 1 (alpha-synuclein, caspase-1, TLR2+ monocytes) differentiated PD cases and controls in both groups, while Component 2 (endotoxin, monocyte TREM2, alpha-synuclein) did so predominantly in the HR group. Component 3 (classical monocytes, alpha-synuclein) also differentiated cases and controls overall in both groups. These findings demonstrate that systemic innate immune changes are present in PD and are greatest in those at higher risk of rapid progression to dementia. Markers associated with PD per-se (alpha-synuclein, caspase-1), differ from those related to cognitive progression and clinical heterogeneity (endotoxin, TREM2, TLR4, classical monocytes, HLA-DR), with mechanistic and therapeutic implications. Alpha-synuclein and caspase-1 are associated, suggesting inflammasome involvement common to all PD, while bacterial translocation associated changes may contribute towards progression to Parkinson's dementia. Additionally, HLA-DR-associated variations in antigen presentation/clearance may modulate existing clinical disease

Designing stem-cell-based dopamine cell replacement trials for Parkinson's disease

Clinical studies of Parkinson’s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO (NCT01898390), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials