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The Human Connectome Project Connectome Dysfunctions in PD

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The Human Connectome Project Connectome Dysfunctions in PD Connectome Dysfunction in Parkinson’s Disease ADEMOLA A. OREMOSU MBBS, MSc, PhD. International Parkinson and Movement Disorder Society | 555 East Wells Street, Suite 1100, Milwaukee WI 53202-3823 USA Tel: +1 414- 276-2145 | www.movementdisorders.org | [email protected] Objectives .Define Connectomes .Describe the basic connnections of the Brain and Connectoctomics .Describe the disorders of Connectomes in Parkinson’s Disease Outline 3 • Parkinson’s disease: What is it? Brief History Clinical and Neuropathological features • Synaptic and structural plasticity changes in PD Brain connectome and connectomics The Human Connectome Project Connectome dysfunctions in PD • Summary/conclusions 4 What is Parkinson’s disease (PD)? 5 •Disorder of the nervous system that primarily affects movements and bodily coordination. Brief History of PD 6 • In 175 AD, Galen described a condition characterised by tremors as ‘Shaking Palsy’. • Modern understanding of PD is attributed to James Parkinson and Jean-Martin Charcot. Types of PD 7 Global epidemiology of PD 8 • The most common movement disorder affecting 1 - 2 % of the general population over the age of 65 years. • The second most common neurodegenerative disorder after Dorsey, E. R., Elbaz, A., Nichols, E., Abd-Allah, F., Abdelalim, A., Adsuar, J. C. & Dahodwala, N. (2018). Global, regional, and national burden of Parkinson's disease, 1990–2016: a systematic analysis for the Alzheimer’s disease (AD) Global Burden of Disease Study 2016. The Lancet Neurology, 17(11), 939-953. Epidemiology of PD in Africa 9 Oluwole, O. G., Kuivaniemi, H., Carr, J. A., Ross, O. A., Olaogun, M. O., Bardien, S., & Komolafe, M. A. (2019). Parkinson's disease in Nigeria: A review of published studies and recommendations for future research. Parkinsonism & related disorders, 62, 36-43. Neuropathological features of PD 10 PD is a multisystem synucleinopathy that produces degeneration in selectively vulnerable neuronal populations, such as dopaminergic neurons in the substantia nigra. Patel, D., Sharma, K., Chauhan, C. S., & Jadon, G. (2014). A CHRONIC, PROGRESSIVE Dickson, D. W. (2018). Neuropathology of Parkinson NEUROLOGICAL DISORDER PARKINSON’S DISEASE-MECHANISMS AND disease. Parkinsonism & related disorders, 46, S30- TREATMENT. Journal of Drug Delivery and Therapeutics, 4(1), 84-91. S33. Neuropathological features of PD 11 Putative organization of the dopaminergic synapse in healthy condition and in PD. Bellucci, A., Mercuri, N. B., Venneri, A., Faustini, G., Longhena, F., Pizzi, M., ... & Spano, P. (2016). Parkinson's disease: from synaptic loss to connectome dysfunction. Neuropathology and applied neurobiology, 42(1), 77-94. Brain Connectomes and Connectomics 12 Fox, M. D. (2018). Mapping symptoms to brain networks with the human connectome. New England Journal of Medicine, 379(23), 2237-2245. Brain Connectomes and Connectomics 13 • The present use of the term connectome refers to the large-scale connections between sections of cortex and possibly the subcortical structures. • Older adults show robust decreases in functional correlations in the default network. • The ability to demonstrate the functional organization of the cortex before cutting into the brain has profound potential towards reducing morbidity of PD and of other NDs. Eggermont, J. J. (2019). The Auditory Brain and Age-related Hearing Impairment. Sughrue, M. E., & Yang, I. (Eds.). (2019). New Techniques for Academic Press. Management of ‘Inoperable’Gliomas. Academic Press. Synaptic and structural plasticity changes in PD 14 • In the brain, the connectivity between neurons (synapses) and their transmission efficiencies determine information processing and storage in neural networks. • Two major processes are responsible for connectivity changes: Structural/architectural plasticity Synaptic plasticity Bellucci, A., Mercuri, N. B., Venneri, A., Faustini, G., Longhena, F., Pizzi, M., ... & Spano, P. (2016). Parkinson's disease: from synaptic loss to connectome dysfunction. Neuropathology and applied neurobiology, 42(1), 77-94. Structural plasticity changes in PD 15 • Structural plasticity can be seen as: The outgrowth and retraction of axons and dendrites primarily taking place during developmental phases or after injuries of the network structure. The process of creating and removing synapses Bellucci, A., Mercuri, N. B., Venneri, A., Faustini, G., Longhena, F., Pizzi, M., ... & Spano, P. (2016). Parkinson's disease: from synaptic loss to connectome dysfunction. Neuropathology and applied neurobiology, 42(1), 77-94. Dendritic spines formation 16 • Spines are highly motile structures, which can appear and disappear on a time scale of hours to days. • Their lifetime depend on their head volume, which correlates with the strength of the excitatory postsynaptic potentials from the corresponding synapse. Fauth M, Worgotter F, Tetzlaff C. The formation of multi-synaptic connections by the Matsuzaki M, Ellis-Davies GC, Nemoto T, Miyashita Y, Iino M, Kasai H. Dendritic spine interaction of synaptic and structural plasticity and their functional consequences. PLoS geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Comput Biol 2015; 11: e1004031. Nat Neurosci 2001; 4: 1086–92 Dendritic spines formation 17 Chen, C. C., Lu, J., & Zuo, Y. (2014). Spatiotemporal Spine remodeling at different stages of an animal’s life. dynamics of dendritic spines in the living brain. Frontiers in neuroanatomy, 8, 28. Synaptic plasticity changes in PD 18 • Synaptic plasticity is the ability of neurons to bring about changes in the connections between them in response to use or disuse. • It can be short-term or long-term. • Striatal spiny projection neurons (SPNs) exhibit long-term potentiation (LTP) and long-term depression (LTD) at corticostriatal synapses • PD is a disorder of synapses and circuits. • Postmortem tissues from PD patients demonstrate apparent alterations in the morphologies of SPNs, such as a significant reduction in the length of the dendritic tree and a loss of spine density Bliss, T. V., & Lømo, T. (1973). Long‐lasting potentiation of synaptic transmission Zucker, R. S., & Regehr, W. G. (2002). Short-term Stephens B, Mueller AJ, Shering AF, Hood SH, Taggart P, Arbuthnott GW, et al. in the dentate area of the anaesthetized rabbit following stimulation of the synaptic plasticity. Annual review of physiology, Evidence of a breakdown of corticostriatal connections in Parkinson’s disease. perforant path. The Journal of physiology, 232(2), 331-356. 64(1), 355-405. Neuroscience. 2005;132:741–54. Synaptic plasticity changes in PD 19 Dendritic spine dynamics in the mouse motor cortex in motor learning and Parkinson’s disease. (A) Illustration of an anesthetized animal under a 2-photon microscope. (B) Targeted area of the skull is marked with circle for in vivo imaging. (C) Blood vasculature under the chronic window was imaged using a charge-coupled device camera and was used as a landmark for relocating the same region during repeated imaging. (D) In vivo 2-photon imaging dendritic spines of layer V pyramidal neurons using Thy1-YFP transgenic mice. Two-photon image with low magnification of dendritic branches in the region indicated in the white box in (C). (E-H) I. Schematic of changes in spine formation and elimination in motor skill training and following dopamine depletion. Xu, T., Wang, S., Lalchandani, R. R., & Ding, J. B. (2017). Motor learning in animal models of Parkinson's disease: Aberrant synaptic plasticity in the motor cortex. Movement Disorders, 32(4), 487-497. Synaptic plasticity changes in PD 20 • Spine formation is modulated by the activation of D2 receptor, and spine stabilization is regulated by D1 receptor activation. • Motor learning induces activity-dependent spine formation and stabilization. • Stabilization of newly formed is proposed to be one of the neural substrates for encoding long-lasting motor memory. Xu, T., Wang, S., Lalchandani, R. R., & Ding, J. B. (2017). Motor learning in animal models of Parkinson's disease: Aberrant synaptic plasticity in the motor cortex. Movement Disorders, 32(4), 487-497. Synaptic plasticity changes in PD 21 • In PD, the lack of dopamine receptor activation leads to increased rates of spine elimination. • Xu et al. (2017) showed that skill training enhanced spine survival in the motor cortex that persists for many months. • Thus, skill training might be beneficial for synaptic plasticity and maintenance of newly formed spines. Xu, T., Wang, S., Lalchandani, R. R., & Ding, J. B. (2017). Motor learning in animal models of Parkinson's disease: Aberrant synaptic plasticity in the motor cortex. Movement Disorders, 32(4), 487-497. Synaptic plasticity changes in PD 22 • Compelling evidences have shown that in PD, there is: • Pathological accumulation of α- synuclein, and • Reduction in NMDA receptor activity • These result in alterations of synaptic and structural plasticity that could then lead to connectome deficits Bellucci, A., Mercuri, N. B., Venneri, A., Faustini, G., Longhena, F., Pizzi, M., ... & Spano, P. (2016). Parkinson's disease: from synaptic loss to connectome dysfunction. Neuropathology and applied neurobiology, 42(1), 77-94. Brain Connectomes and Connectomics 23 • The “connectome” is a name coined in analogy to the genome, and basically comprises the structural, functional, and affective neural networks in the brain. • It is simply put, a comprehensive map of neural connections in the brain • Connectomics borrows the “-omics” suffix from genomics as
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