Lewy body disease or diseases with Lewy bodies?

Abstract

The current nosological concept of α-synucleinopathies characterized by the presence of Lewy bodies (LBs) includes Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB), for which the term “Lewy body disease” (LBD) has recently been proposed due to their considerable clinical and pathological overlap. However, even this term does not seem to describe the true nature of this group of diseases. The subsequent discoveries of α-synuclein (αSyn), SNCA gene, and the introduction of new immunohistochemical methods have started intensive research into the molecular-biological aspects of these diseases. In light of today’s knowledge, the role of LBs in the pathogenesis and classification of these nosological entities remains somewhat uncertain. An increasingly more important role is attributed to other factors as the presence of various LBs precursors, post-translational αSyn modifications, various αSyn strains, the deposition of other pathological proteins (particularly β-amyloid), and the discovery of selective vulnerability of specific cells due to anatomical configuration or synaptic dysfunction. Resulting genetic inputs can undoubtedly be considered as the main essence of these factors. Molecular–genetic data indicate that not only in PD but also in DLB, a unique genetic architecture can be ascertained, predisposing to the development of specific disease phenotypes. The presence of LBs thus remains only a kind of link between these disorders, and the term “diseases with Lewy bodies” therefore results somewhat more accurate.

In Pancreatic Adenocarcinoma Alpha-Synuclein Increases and Marks Peri-Neural Infiltration

“…The present study focuses on a specific autophagy-dependent substrate, the protein α-syn, which was only investigated in neurodegenerative disorders so far. In fact, an increase in α-syn is concomitant with autophagy failure in the course of specific degenerative disorders named synucleinopathies [ 57 ]. However, very recent findings indicate an increased amount of α-syn in neural crest-derived malignancies such as melanoma, where α-syn promotes cell proliferation and tumor spreading [ 25 , 26 , 58 ].…”

Natural language processing and modeling of clinical disease trajectories across brain disorders

“…These differential signs and symptoms were clearly corroborated by this study. Importantly, there is considerable debate whether these alpha-synucleinopathies are merely different manifestations of the same pathophysiological processes, in which the brain regions that are most affected determine the clinical manifestation or that there are qualitative differences in the underlying pathophysiology 6 . We identified clear differential temporal and survival responses, between these four conditions after 'Bradykinesia' was first observed, which manifested at a considerably younger age in MSA, and was associated with shorter survival in MSA, and DLB, compared to PD and PDD.…”

“…A rapidly increasing number of studies focuses on the relationship between neuropathology, and clinical manifestation of brain disorders both within and between disorders such as AD-subtypes 31 , complex and comorbid dementias 3 , FTD-subtypes 28 , alpha-synucleinopathies 6 and mental illnesses 32 . The relationship between neuropathology, clinical syndromes, and associated signs and symptoms is often complex, in which many signs and symptoms can occur in many disorders, but the frequency and the temporal profiles of these signs and symptoms generally tends to differ between neuropathological conditions.…”

“…MSA is also an alpha-synucleinopathy, which primarily manifests by motor disturbances without cognitive and or psychiatric difficulties. There is considerable debate whether these alpha- synucleinopathies are different manifestations of the same underlying neuropathology manifesting in different brain regions, or that there are unique neuropathological processes associated with these disorders 6 . Temporally, we found that 'Bradykinesia' was observed significantly earlier in MSA than in the other disorders.…”

“…preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 23, 2022. ; https://doi.org/10.1101/2022.09. 22.22280158 doi: medRxiv preprint disorders 4,5 and frequent and complex comorbidity patterns [6][7][8] . Moreover, large discrepancies between clinical and neuropathological diagnosis were frequently observed, in which up to a third of cases with a specific dementia were misdiagnosed [9][10][11][12] .…”