Title of project or programme

Neurology

Principal Investigators of project/programme grant
Title Forname Surname Institution Country
Professor David Brooks MRC Clinical Sciences Centre UK
Address of institution of lead PI
Institution MRC Clinical Sciences Centre
Street Address Imperial College London, Hammersmith Hospital Campus, Du Cane Road
City London
Postcode W12 0NN
Country
  • United Kingdom
Source of funding information

Medical Research Council

Total sum awarded (Euro)

12862766.93

Start date of award

01-04-2005

Total duration of award in months

60

The project/programme is most relevant to
  • Parkinson’s disease
  • Huntington’s disease
Keywords
Research abstract in English

To investigate in vivo with PET/MRI activation and PET ligand studies:

* The functional anatomy of motor control in health and disease and its modulation by incentives and aversive stimuli.

* Changes in release of dopamine and other modulatory neurotransmitters, and opening of voltage gated ion channels during different aspects of motor function.

* The dysfunctional anatomy and transmitter release underlying bradykinesia and involuntary movements in Parkinson’s and Huntington’s diseases and dystonias.

* Central mechanisms of adaptation to lesions of the basal ganglia and motor pathways.

* Resting patterns of altered dopa and glucose metabolism and receptor binding underlying idiopathic and genetic forms of Parkinson’s disease, atypical parkinsonian disorders, and involuntary movement disorders

* The glial response to cortical and subcortical neurodegenerations.

* Levels of abnormal protein aggregation (beta amyloid, tau, synuclein deposition) in cortical and subcortical dementias. Using PET as a biomarker, to determine in vivo the efficacy of:

* Putative neuroprotective agents in modifying progression of subcortical degenerations disorders and influencing glial activation and amyloid deposition.

*Nerve growth factors in restoring function in Parkinson’s disease and, in the future, other subcortical neurodegenerations.

* Cell implants (fetal midbrain and striatal/retinal pigment epithelial/carotid body/transformed fibroblasts/neural progenitor) in restoring function in Parkinson’s and Huntington’s diseases.

Lay Summary

    Principal Investigators

    Professor DJ Brooks

    Institution

    Imperial College London

    Contact information of lead PI

    Country

    United Kingdom

    Title of project or programme

    Neurology

    Source of funding information

    MRC

    Total sum awarded (Euro)

    € 2,013,973

    Start date of award

    05/05/2011

    Total duration of award in years

    5.0

    The project/programme is most relevant to:

    Alzheimer's disease and other dementias | Parkinson's disease and PD-related disorders | Huntington's disease

    Keywords

    Research Abstract

    This programme, based at Imperial College London, targets the use of positron emission tomography (PET) to image the functional changes associated with Alzheimer‘s, Parkinson‘s, and Huntington‘s diseases. In subjects who have amnestic mild cognitive impairment and so are at risk of progressing to dementia the time course of amyloid deposition and microglial activation (inflammation) and relationship between these pathologies is being examined. Brain imaging findings with PET are being correlated with amyloid and cytokine levels in spinal fluid and plasma proteomic profiles. The time course and pattern of amyloid deposition in carriers of gene mutations predisposing to Alzheimer‘s disease (presenelin and APP) is also being tracked. The efficacy of anti-amyloid strategies such as passive immunotherapies is being trialled using PET amyloid imaging as a proof of mechanism. Parkinson‘s disease (PD) patients with memory or gait difficulties are also at risk of developing dementia. Again, the prevalence of cortical microglial activation and amyloid deposition in these high risk cases and the relationship between these pathologies is being examined. Asymptomatic LRRK2 and glucocerebrosidase A gene mutation carriers at risk for PD are also being ascertained to determine the time course of inflammatory changes in the brainstem. PD is also associated with other non-motor problems such as sleep disorders, fatigue, depression, and impusle control disorders. PET is being used to study the relative contributions of brainstem and limbic dopaminergic and serotonergic dysfunction to these syndromes in PD in the belief that it may throw light on the mechanisms underlying these problems in the general population. The implantation of fetal midbrain cells into the putamen of advanced PD patients has previously been associated with variable efficacy and disabling graft-associated involuntary movements (dyskinesias). We are studying the mechanisms underlying development of thesias. Additionally, a trial using PET to measure graft function in transplanted patients with early rather than advanced PD is underway. Huntington‘s disease (HD) gene carriers inevitably develop symptoms but it is now possible to detect functional changes with PET some years ahead of clinical disease manifestation. The programme is examining the time course of striatal microglial activation in asymptomatic HD gene carrtiers and how this correlates with spinal fluid and plasma levels of cytokines and other inflammatory markers. The role of cannabinoid CB1 radioligands as markers of striatal degeneration in HD is also being explored. In summary, this MRC programme is designed to determine the efficacy of functional imaging as a prognostic biomarker of dementia, to determine the role of microglial activation in driving neurodegeneration, and to provide proof of mechanism when putative neuroprotective and restorative therapies are being trialled.

    Lay Summary

    Further information available at:

Types: Investments > €500k
Member States: United Kingdom
Diseases: Huntington's disease, Parkinson's disease & PD-related disorders
Years: 2011
Database Categories: N/A
Database Tags: N/A

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