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A quantitative study of α-synuclein pathology in fifteen cases of dementia associated with Parkinson disease

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

The α-synuclein-immunoreactive pathology of dementia associated with Parkinson disease (DPD) comprises Lewy bodies (LB), Lewy neurites (LN), and Lewy grains (LG). The densities of LB, LN, LG together with vacuoles, neurons, abnormally enlarged neurons (EN), and glial cell nuclei were measured in fifteen cases of DPD. Densities of LN and LG were up to 19 and 70 times those of LB, respectively, depending on region. Densities were significantly greater in amygdala, entorhinal cortex (EC), and sectors CA2/CA3 of the hippocampus, whereas middle frontal gyrus, sector CA1, and dentate gyrus were least affected. Low densities of vacuoles and EN were recorded in most regions. There were differences in the numerical density of neurons between regions, but no statistical difference between patients and controls. In the cortex, the density of LB and vacuoles was similar in upper and lower laminae, while the densities of LN and LG were greater in upper cortex. The densities of LB, LN, and LG were positively correlated. Principal components analysis suggested that DPD cases were heterogeneous with pathology primarily affecting either hippocampus or cortex. The data suggest in DPD: (1) ratio of LN and LG to LB varies between regions, (2) low densities of vacuoles and EN are present in most brain regions, (3) degeneration occurs across cortical laminae, upper laminae being particularly affected, (4) LB, LN and LG may represent degeneration of the same neurons, and (5) disease heterogeneity may result from variation in anatomical pathway affected by cell-to-cell transfer of α-synuclein.

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Abbreviations

Aβ:

β-Amyloid

AD:

Alzheimer’s disease

AG:

Argyrophilic grains

AGD:

Argyrophilic grain disease

ANOVA:

Analysis of variance

CA:

Cornu Ammonis

CERAD:

Consortium to establish a registry of Alzheimer’s disease

CG:

Cingulate gyrus

DLB:

Dementia with Lewy bodies

DPD:

Dementia associated with Parkinson’s disease

EC:

Entorhinal cortex

EN:

Abnormally enlarged neurons

LB:

Lewy bodies

LN:

Lewy neurites

LG:

Lewy grains

MFG:

Middle frontal gyrus

MSA:

Multiple system atrophy

NCI:

Neuronal cytoplasmic inclusion

NIA:

National Institute on Aging

PC:

Principal component

PCA:

Principal components analysis

PD:

Parkinson’s disease

pTDP-43:

Phosphorylated TDP-43

PHG:

Parahippocampal gyrus

SN:

Substantia nigra

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Acknowledgments

We thank Deborah Carter, Toral Patel, and Lisa Taylor-Reinwald of the Betty Martz Laboratory for Neurodegenerative Research for expert assistance and we thank the families of patients whose generosity made this research possible. Support for this work was provided by grants from the National Institute on Aging of the National Institutes of Health (P50-AG05681, P01-AG03991), National Institute of Neurologic Diseases and Stroke (NS075321, NS41509, NS058714), NIH (ULITR000488), the Hope Center for Neurological Disorders, the Buchanan Fund, the Charles F. & Joanne Knight Alzheimer’s Disease Research Center, the American Parkinson Disease Association (APDA) Advanced Research Centre for Parkinson Disease at Washington University in St Louis, The Greater St Louis Chapter of the APDA, the McDonnell Center for Molecular and Cellular Neurobiology, and the Barnes-Jewish Foundation (Elliot-Stein Family Fund and Parkinson Disease Research Fund).

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Authors and Affiliations

  1. Vision Sciences, Aston University, Birmingham, B4 7ET, UK

    Richard A. Armstrong

  2. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA

    Paul T. Kotzbauer, Joel S. Perlmutter, Meghan C. Campbell & Nigel J. Cairns

  3. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA

    Paul T. Kotzbauer

  4. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA

    Paul T. Kotzbauer, Joel S. Perlmutter & Nigel J. Cairns

  5. Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA

    Joel S. Perlmutter & Meghan C. Campbell

  6. Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, USA

    Joel S. Perlmutter

  7. Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, USA

    Joel S. Perlmutter

  8. Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, USA

    Joel S. Perlmutter

  9. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Kyle M. Hurth, Robert E. Schmidt & Nigel J. Cairns

  10. Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA

    Nigel J. Cairns

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  1. Richard A. Armstrong
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Correspondence to Richard A. Armstrong.

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Armstrong, R.A., Kotzbauer, P.T., Perlmutter, J.S. et al. A quantitative study of α-synuclein pathology in fifteen cases of dementia associated with Parkinson disease. J Neural Transm 121, 171–181 (2014). https://doi.org/10.1007/s00702-013-1084-z

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  • DOI: https://doi.org/10.1007/s00702-013-1084-z

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