I’ve decided to organize my topic starting with an introduction, which will include some background information on Dementia with Lewy bodies. Then, I’ll go into the pathology of the disease, where I’ll first mention a-synuclein. This protein is central to the disease, so I’ll also include a brief explanation of the role it plays. I searched the literature for current treatments and found that they are not curative, only preventative. In recent papers on the disease, I found that research involving a-synuclein comes up frequently. Since this area seems to be where the the field is focused, my next topic will explore the major findings involving a-synuclein and the disease. I’ll end by looking into what future research might entail and touch on research not involving a-synuclein.
Overview of themes:
What is Dementia with Lewy Bodies: An Introduction to the Disease
In order to understand what follows, the reader first needs a summary of the disease. This means explaining what the disease is, how it works, and why research into it is important. Dementia with Lewy bodies (DLB) and Parkinson’s disease are very similar, and it’s almost impossible to find literature that mentions DLB without also referring to Parkinson’s. Some of the papers that I explore focus primarily on Parkinson’s, with DLB as an afterthought. However, this doesn’t mean that the research isn’t relevant to this disease, mainly because they share such similarity. It may be necessary to expand further on this part.
The Pathology of DLB
Dementia with Lewy bodies in part a group of neurodegenerative diseases called a-synucleinopathies, which are characterized by aggregated alpha-synuclein, a protein abundant in the brain. This aggregation affects synapses both pre and post-synaptically. Understanding how the aggregates form is the first step in understanding pathogenesis in Lewy body diseases.
Treatments: What is currently being done
As of now, there is no disease modifying drug that exists. Current treatments aim to prevent or slow production of aggregates. Since a major feature of Lewy bodies is cholinergic dysfunction, this main treatment is cholinesterase inhibitors (Taylor et al, 2017).
Recent findings in DLB
Major finding 1: research has pointed toward evidence that a-synuclein may propagate in a prion like way, which in turn has led to interest in the mechanism of propagation as a target for new therapies (Kim et al, 2014). Major finding 2: Research into differences between a-synuclein in Lewy bodies and normal cells led to the discovery of a phosphorylated serine, Ser129 in Lewy bodies a-synuclein. The phosphorylation is proposed to mediate aggregation and neurotoxicity with higher levels corresponding to greater severity (Swirski et al, 2014). Major finding 3: reducing a-synuclein degrading enzymes may contribute to disease. Kallikrein-6 and calpain-1 are two proteases found to be reduced in Lewy body dementias (Miners et al, 2014). Major finding 4: a recent large scale genetic study revealed the possibility that dementia with Lewy bodies may have a heritable component of about 36% (Guerreiro et al, 2018). Major finding 5: a-synuclein exists in an equilibrium between monomer and tetramer/multimers. Mutants are unable to multimerize, leading to excess monomers which induces vesicle clustering resembling what’s seen in Lewy bodies (Miners et al, 2014).
Guerreiro et al. 2018. The Lancet Neurology 17 (1): 64–74. https://doi.org/10.1016/S1474-4422(17)30400-3.
Kim, Woojin Scott, Katarina Kågedal, and Glenda M. Halliday. 2014. “Alpha-Synuclein Biology in Lewy Body Diseases.” Alzheimer’s Research & Therapy 6 (October): 73. https://doi.org/10.1186/s13195-014-0073-2.
Miners, J. Scott, Ruth Renfrew, Marta Swirski, and Seth Love. 2014. “Accumulation of α-Synuclein in Dementia with Lewy Bodies Is Associated with Decline in the α-Synuclein-Degrading Enzymes Kallikrein-6 and Calpain-1.” Acta Neuropathologica Communications 2 (December): 164. https://doi.org/10.1186/s40478-014-0164-0.
Miners, Scott, Hayley Moulding, Rohan de Silva, and Seth Love. 2014. “Reduced Vascular Endothelial Growth Factor and Capillary Density in the Occipital Cortex in Dementia with Lewy Bodies.” Brain Pathology 24 (4): 334–43. https://doi.org/10.1111/bpa.12130.
Swirski, Marta, J. Scott Miners, Rohan de Silva, Tammaryn Lashley, Helen Ling, Janice Holton, Tamas Revesz, and Seth Love. 2014. “Evaluating the Relationship between Amyloid-β and α-Synuclein Phosphorylated at Ser129 in Dementia with Lewy Bodies and Parkinson’s Disease.” Alzheimer’s Research & Therapy 6 (December): 77. https://doi.org/10.1186/s13195-014-0077-y.
Taylor, John-Paul, Daniel Collerton, Fiona LeBeau, and Elaine Perry. 2017. “Cholinergic Pathology in Dementia with Lewy Bodies.” In Dementia with Lewy Bodies, 23–39. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55948-1_3.