Dementia risk in Parkinson's disease is associated with interhemispheric connectivity loss and determined by regional gene expression

Angeliki Zarkali; Peter McColgan; Mina Ryten; Regina H Reynolds; Louise-Ann Leyland; Andrew J Lees; Geraint Rees; Rimona S Weil

doi:10.1016/j.nicl.2020.102470

Dementia risk in Parkinson's disease is associated with interhemispheric connectivity loss and determined by regional gene expression

Neuroimage Clin. 2020:28:102470. doi: 10.1016/j.nicl.2020.102470. Epub 2020 Oct 15.

Authors

Angeliki Zarkali¹, Peter McColgan², Mina Ryten³, Regina H Reynolds³, Louise-Ann Leyland⁴, Andrew J Lees⁵, Geraint Rees⁶, Rimona S Weil⁷

Affiliations

¹ Dementia Research Centre, University College London, 8-11 Queen Square, London WC1N 3AR, UK. Electronic address: a.zarkali@ucl.ac.uk.
² Huntington's Disease Centre, University College London, Russell Square House, London WC1B 5EH, UK.
³ NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK; Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, UK; Department of Neurodegenerative Disease, UCL Institute of Neurology, 10-12 Russell Square House, London WC1B 5EH, UK.
⁴ Dementia Research Centre, University College London, 8-11 Queen Square, London WC1N 3AR, UK.
⁵ Reta Lila Weston Institute of Neurological Studies, 1 Wakefield Street, London WC1N 1PJ, UK.
⁶ Institute of Cognitive Neuroscience, University College London, 17-19 Queen Square, London WC1N 3AR, UK; Wellcome Centre for Human Neuroimaging, University College London, 12 Queen Square, London WC1N 3AR, UK.
⁷ Dementia Research Centre, University College London, 8-11 Queen Square, London WC1N 3AR, UK; Wellcome Centre for Human Neuroimaging, University College London, 12 Queen Square, London WC1N 3AR, UK; Movement Disorders Consortium, University College London, London WC1N 3BG, UK.

Abstract

Parkinson's dementia is a common and devastating part of Parkinson's disease. Whilst timing and severity vary, dementia in Parkinson's is often preceded by visual dysfunction. White matter changes, representing axonal loss, occur early in the disease process. Clarifying which white matter connections are affected in Parkinson's with visual dysfunction and why specific connections are vulnerable will provide important mechanistic insights. Here, we use diffusion tractography in 100 Parkinson's patients (33 low visual performers) and 34 controls to identify patterns of connectivity loss in Parkinson's with visual dysfunction. We examine the relationship between regional transcription and connectivity loss, using the Allen Institute for Brain Science transcriptome atlas. We show that interhemispheric connections are preferentially affected in Parkinson's low visual performers. Interhemispheric connection loss was associated with downweighted genes related to the smoothened signalling pathway (enriched in glutamatergic neurons) and upweighted metabolic genes. Risk genes for Parkinson's but not Alzheimer's or Dementia with Lewy bodies were over-represented in upweighted genes associated with interhemispheric connection loss. Our findings suggest selective vulnerability in Parkinson's patients at highest risk of dementia (those with visual dysfunction), where differences in gene expression and metabolic dysfunction, affecting longer connections with higher metabolic burden, drive connectivity loss.

Keywords: Connectomics; Diffusion weighted imaging; Parkinson’s disease; Parkinson’s disease dementia; Regional gene expression; White matter.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain
Dementia*
Gene Expression
Humans
Parkinson Disease* / genetics
White Matter* / diagnostic imaging

Abstract

Publication types

MeSH terms

Grants and funding