Junior Research Award:
Reduced synaptic density in cortical and subcortical gray matter is associated with mild parkinsonian signs in healthy elderly: a [11C]UCB-J PET study
Receiving an MDS Junior Research Award is a huge honor, and I am grateful for the opportunity to share our research with the MDS community during its international conference. This project could not have been possible without the efforts of our participants1,2, who I want to thank warmly. The audience’s applause at the end of my presentation flooded an attempt to thank my promoters Prof. Vandenbulcke, Dr. Emsell, and Prof. Bouckaert on stage, so let me set it right by thanking you here for your guidance and support. Many thanks also to my co-authors on the abstract, especially to Maarten Laroy and Thomas Vande Casteele for your exceptional teamwork within the L3D study.
Our research was inspired by the observation of subtle motor signs in the healthy control participants from the L3D study2. Most adults experience some decline in motor function over time, which is said to be part of “normal aging.” However, in 15% to 40% of healthy people above the age of 65, this presents as mild parkinsonian signs (MPS), which are similar to parkinsonism but subtle and not fulfilling disease criteria3,4. The relevance of MPS lies in their association with dysfunction in daily life, morbidity and death, often due to falls. Moreover, MPS are a risk factor for Parkinson’s disease and Alzheimer’s dementia. It remains unclear whether MPS are a consequence of normal brain aging or prodromes of neurodegenerative disease. Previous studies investigating the pathophysiology of MPS inconsistently found local involvement of (dopaminergic) motor regions, whereas others describe generalized brain degeneration such as grey matter volume (GMV) loss or white matter lesions (WML)3,4. Given that synaptic dysfunction represents an important pathway to neurodegenerative disease and functional impairment5, we capitalized on the recent development of the synaptic vesicle 2A binding [11C] UCB-J PET tracer6 to investigate the role of synaptic density in MPS.
The aim of our study was to investigate whether lower synaptic density in (sub)cortical motor regions of the brain is associated with MPS in healthy older adults. In the majority of the 59 included participants (age > 50, mean 68 years), we observed subtle motor symptoms with a mean MDS-UPDRSIII score of 3.4. Regression models corrected for age, sample, GMV and WML showed that lower synaptic density in cortical regions (frontal, parietal, occipital and temporal lobe), subcortical grey matter (caudate, thalamus, substantia nigra), and the cerebellar grey matter was associated with a higher MDS-UPDRSIII score. Total WML load did not contribute to the total MDS-UPDRSIII score. We conclude that MPS in healthy aging are associated with widespread lower cortico-subcortical synaptic density, independent of WML and GMV. This finding overlaps partly with synaptic density findings in Parkinson’s disease,1,7,8 but longitudinal research is needed to clarify whether this is due to an inborn vulnerability of brain synapses, an acquired state, or prodromal Parkinson’s disease. To understand what is going on in brain diseases of old age, we first have to understand what is going on in normal brain aging.
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Delva A, Van Weehaeghe D, Koole M, Van Laere K, Vandenberghe W. loss of presynaptic terminal integrity in the substantia nigra in early Parkinson's disease. Mov Disord. 2020 Nov;35(11):1977-1986.
Emsell L, Laroy M, Van Cauwenberge M, Vande Casteele T, Vansteelandt K, Van Laere K, Sunaert S, Van den Stock J, Bouckaert F, Vandenbulcke M. The Leuven late life depression (L3D) study: PET-MRI biomarkers of pathological brain ageing in late-life depression: study protocol. BMC Psychiatry. 2021 Jan 28;21(1):64.
Buchanan SM, Richards M, Schott JM, Schrag A. Mild Parkinsonian Signs: A Systematic Review of Clinical, Imaging, and Pathological Associations. Mov Disord. 2021;36(11):2481-93.
Louis ED, Bennett DA. Mild Parkinsonian signs: An overview of an emerging concept. Mov Disord. 2007;22(12):1681-8.
Kulkarni AS, Burns MR, Brundin P, Wesson DW. Linking α-synuclein-induced synaptopathy and neural network dysfunction in early Parkinson’s disease. Brain Communications 2022;4(4):fcac165.
Carson RE, Naganawa M, Toyonaga T, Koohsari S, Yang Y, Chen MK, Matuskey D, Finnema SJ. imaging of synaptic density in neurodegenerative disorders. J Nucl Med. 2022 Jun;63(Suppl 1):60S-67S
Matuskey D, Tinaz S, Wilcox KC, Naganawa M, Toyonaga T, Dias M, et al. Synaptic changes in Parkinson Disease Assessed with in vivo Imaging. Ann Neurol. 2020;87(3):329-38.
Wilson H, Pagano G, de Natale ER, Mansur A, Caminiti SP, Polychronis S, et al. Mitochondrial complex 1, sigma 1, and synaptic vesicle 2A in early drug-naive Parkinson's disease. Mov Disord. 2020;35(8):1416-27.
Dr. Margot Van Cauwenberge is a clinical neurologist and PhD student at the Leuven Brain Institute, Belgium. She received her neurology training at the University Hospital Gent (Belgium), the University Hospital RWTH Aachen (Germany) and the Radboud UMC (Nijmegen, the Netherlands). Guided by her supervisor Prof. Dr. Mathieu Vandenbulcke at the KU Leuven Center for Neuropsychiatry, her PhD project focuses on psychomotor retardation in late-life depression. Within the Leuven Late Life Depression (L3D) study, she uses multimodal PET-MR brain imaging to study brain changes associated with aberrant motor function in old age, quantified with digital tools such as tablet drawing and smartwatch technology. She advocates a holistic approach to medicine, which unifies neurology and psychiatry as disciplines studying the brain.