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Loss of phosphodiesterase 4 in Parkinson disease

Relevance to cognitive deficits

  1. Marios Politis, MD, PhD
  1. From the Neurodegeneration Imaging Group (F.N., H.W., G.P., M.P.) and Department of Neuroimaging (M.A.M., E.A.R.), Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London; Imanova Ltd., Centre for Imaging Sciences (C.C., G.E.S., R.N.G., E.A.R.), and Division of Brain Sciences, Imperial College London (R.N.G), Hammersmith Hospital; and Sobell Department of Motor Neuroscience (T.F.), UCL Institute of Neurology, London, UK.
  1. Correspondence to Dr. Politis: marios.politis{at}kcl.ac.uk
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  1. NONE

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. (1) UCB, funding for travel to conference (MDS 2016 Berlin)

Editorial Boards:

  1. (1) International Journal of Medical Imaging, Associate Editor, 2014-2017 (2) Biological Markers and Guided Therapy, Associate Editor, 2014-2017 (3) Clinical Medicine Research, Associate Editor, 2014-2017 (4) Frontiers in Neurology, Editorial Board, 2015-2017 (5) Frontiers Physiology, Editorial Board, 2013-2017 (6) Journal of Neurology and Experimental Neural Science, Editorial Board, 2014-2017 (7) SM Journal of Neurology and Neuroscience, Editorial Board, 2015-2017

Patents:

  1. (1) Adrenoceptors Antagonists for the Prevention and Treatment of Neurodegenerative Conditions (co-inventor) ? U.S. No. 61/840,381 filed June 27, 2013.

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

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Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) The Edmond and Lily Safra Foundation

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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Patents:

  1. US7615755 (2009/11/10): Photon counting detector with comparator and switchover rate analyzer US13/998,390 (2013/10/29) : Method for improved estimation of tracer uptake in physiological image volumes

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. Employed at Imanova Ltd as PET Analyst from 04/2013 to 03/2017.

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

Scientific Advisory Boards:

  1. 1. None 2. Forum Pharmaceuticals Scientific Advisory Board

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. 1. Journal of Psychopharmacology, Editorial Board Member, 2014- 2. Psychopharmacology, Editorial Advisory Board Member, 2013-

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. 1. Taisho pharmaceuticals

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. 1. Lundbeck 2. Takeda 3. Hofmann La Roche

Research Support, Government Entities:

  1. 1. Medical Research Council UK, MR/K015192, PI, 2014-2016

Research Support, Academic Entities:

  1. NONE

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  1. NONE

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  1. NONE

Employment, Commercial Entity:

  1. (1) Imanova Ltd., Head of PET Analysis, 5 years.

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. (1) Employee of Imanova Ltd.

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. (1) MIAKAT Ltd.

License fee payments, Technology or Inventions:

  1. (1) MIAKAT software, license fee royalties.

Royalty Payments, Technology or Inventions:

  1. (1) MIAKAT software, license fee royalties.

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. Imanova Ltd

Consultancies:

  1. (1) GSK (2) Abbvie (3) UCB

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

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  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

Employment, Commercial Entity:

  1. Chief Medical Officer, Imanova Ltd

Consultancies:

  1. Consultant - Opiant Pharmaceuticals

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Imanova conducts contract research for a variety of commercial organisations, including most big Pharma

Research Support, Government Entities:

  1. Imanova provides imaging facilities for for academic researchers supported by a variety of funding bodies

Research Support, Academic Entities:

  1. King's College, London, UK

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. I am a stockholder of GlaxoSmithKline

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  1. NONE

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Scientific Advisory Boards:

  1. (1) Served on SAB for Oxford Biomedica, (2) Served on SAB for Abbvie Pharmaceuticals (3) Served on DSMB for Oxford Biomedica

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. (1) Speaker Honoraria from Medtronic. (2) Speaker Honorarium for UCB Pharma

Editorial Boards:

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Employment, Commercial Entity:

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) Grant funding from Michael J Fox Foundation (2) Grant funding from Brain Research Trust

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Journal of Parkinson's disease, Associate editor, 2015 Frontiers in Neurology, Associate Editor, 2016

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

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  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

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  1. NONE

Research Support, Government Entities:

  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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  1. NONE

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Abstract

Objective: To assess in vivo the expression of phosphodiesterase 4 (PDE4) and its relevance to cognitive symptoms in patients with Parkinson disease (PD) using [11C]rolipram PET.

Methods: We studied 12 levodopa-treated patients with PD with no concurrent diagnosis of mild cognitive impairment or dementia. Their data were compared with those from 12 healthy controls. All participants underwent neuropsychiatric and cognitive assessment using the Cambridge Neuropsychological Test Automated Battery. Parametric images of [11C]rolipram volume of distribution (VT) values were determined with the Logan plot.

Results: Patients with PD performed worse than healthy controls in cognitive examinations assessing psychomotor speed, episodic memory, and spatial working memory and executive function. Patients with PD showed reductions in [11C]rolipram VT compared to healthy controls, in the caudate (28%), thalamus (23%), hypothalamus (32%), and cortex (16%). Within thalamic subregions, [11C]rolipram VT values in patients with PD were decreased by 12%–32%, with most marked decreases observed in prefrontal and temporal thalamic nuclei, whereas motor nuclei were less affected. Within the cortex, [11C]rolipram VT values in patients with PD were decreased by 11%–20%, with most marked decreases observed in posterior dorsolateral frontal cortex, medial frontal cortex, and supplementary motor area, whereas orbitofrontal cortex was less affected. Worse performance in spatial working memory correlated with lower [11C]rolipram VT values in posterior dorsolateral frontal cortex, medial frontal cortex, supplementary motor area, precentral gyrus, caudate, and prefrontal thalamic nuclei.

Conclusions: Our findings demonstrate loss of PDE4 expression in the striato-thalamo-cortical circuit, which is associated with deficits of spatial working memory in patients with PD.

  • Received November 17, 2016.
  • Accepted in final form April 11, 2017.
  1. Published online before print July 12, 2017, doi: 10.1212/WNL.0000000000004201 Neurology 10.1212/WNL.0000000000004201
  1. » Abstract
  2. Full Text (PDF)
  3. Data Supplement
  4. Accompanying Editorial

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