caa a22 4500 445377410 CHVBK 20180317143007.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s00702-010-0482-8 doi (NATIONALLICENCE)springer-10.1007/s00702-010-0482-8 Neuropathology of sporadic Parkinson disease before the appearance of parkinsonism: preclinical Parkinson disease [Elektronische Daten] [Isidre Ferrer, Anna Martinez, Rosa Blanco, Ester Dalfó, Margarita Carmona] Parkinson disease (PD) is no longer considered a complex motor disorder characterized by parkinsonism but rather a systemic disease with variegated non-motor deficits and neurological symptoms, including impaired olfaction, sleep disorders, gastrointestinal and urinary abnormalities and cardiovascular dysfunction, in addition to other symptoms and signs such as pain, depression and mood disorders. Many of these alterations appear before or in parallel with motor deficits and then worsen with disease progression. Although there is a close relation between motor symptoms and the presence of Lewy bodies (LBs) and neurites filled with abnormal α-synuclein, other neurological alterations are independent of LBs, thereby indicating that different mechanisms probably converge in the degenerative process. This review presents cardinal observations at very early stages of PD and provides personal experience based on the study of a consecutive series of brains with PD-related pathology and without parkinsonism, mainly cases categorized as stages 2-3 of Braak. Alterations in the substantia nigra, striatum and frontal cortex in pPD are here revised in detail. Early modifications in the substantia nigra at pre-motor stages of PD (preclinical PD: pPD) include abnormal small aggregates of α-synuclein which is phosphorylated, nitrated and oxidized, and which exhibits abnormal solubility and truncation. This occurs in association with a plethora of altered molecular events including increased oxidative stress, altered oxidative stress responses, altered balance of L-ferritin and H-ferritin, reduced expression of neuronal globin α and β chains in neurons with α-synuclein deposits, increased expression of endoplasmic reticulum stress markers, increased p62 and ubiquitin immunoreactivity in relation to α-synuclein deposits, and altered distribution of LC3 and other autophagosome/lysosome markers. In spite of the relatively small decrease in the number of dopaminergic neurons in the substantia nigra, which does not reach thresholds causative of parkinsonism, levels of tyrosine hydroxylase and cannabinoid 1 receptor are reduced, whereas levels of adenosine receptor 2A are increased in the caudate in pPD. Moreover, biochemical alterations are also present in the cerebral cortex (at least in the frontal cortex) in pPD including increased oxidative stress and oxidative damage to proteins α-synuclein, β-synuclein, superoxide dismutase 2, aldolase A, enolase 1, and glyceraldehyde dehydrogenase, among others, indicating post-translational modifications of PD-related proteins, and suggesting altered function of pathways involved in glycolysis and energy metabolism in the cerebral cortex in pPD. Current evidence suggests convergence of several altered metabolic pathways leading to chronic neuronal dysfunction, mainly manifested as sub-optimal energy metabolism, altered synaptic function, oxidative and endoplasmic reticulum stress damage and corresponding altered responses, among others. By understanding that these alterations occur at very early stages of PD and that neuronal fatigue and exhaustion may precede, for years, cell death and neuronal loss, we may direct therapeutic strategies towards the prevention and delay of disease progression starting at pre-parkinsonian stages of PD. Springer-Verlag, 2010 Preclinical Parkinson disease nationallicence Incidental Lewy body disease nationallicence Oxidative stress nationallicence Endoplasmic reticulum stress nationallicence Haemoglobin nationallicence Mitochondria nationallicence Olfaction nationallicence Cerebral cortex nationallicence Striatum nationallicence Synuclein nationallicence Glycolysis nationallicence Ferrer Isidre Institut de Neuropatologia, Servei Anatomia Patològica, CIBERNED, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, carrer Feixa LLarga sn, 08907, Hospitalet de LLobregat, Spain aut Martinez Anna Institut de Neuropatologia, Servei Anatomia Patològica, CIBERNED, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, carrer Feixa LLarga sn, 08907, Hospitalet de LLobregat, Spain aut Blanco Rosa Institut de Neuropatologia, Servei Anatomia Patològica, CIBERNED, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, carrer Feixa LLarga sn, 08907, Hospitalet de LLobregat, Spain aut Dalfó Ester Institut de Neuropatologia, Servei Anatomia Patològica, CIBERNED, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, carrer Feixa LLarga sn, 08907, Hospitalet de LLobregat, Spain aut Carmona Margarita Institut de Neuropatologia, Servei Anatomia Patològica, CIBERNED, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, carrer Feixa LLarga sn, 08907, Hospitalet de LLobregat, Spain aut Journal of Neural Transmission Springer Vienna 118/5(2011-05-01), 821-839 0300-9564 118:5<821 2011 118 702 https://doi.org/10.1007/s00702-010-0482-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00702-010-0482-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Ferrer Isidre Institut de Neuropatologia, Servei Anatomia Patològica, CIBERNED, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, carrer Feixa LLarga sn, 08907, Hospitalet de LLobregat, Spain aut NATIONALLICENCE 700 1- Martinez Anna Institut de Neuropatologia, Servei Anatomia Patològica, CIBERNED, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, carrer Feixa LLarga sn, 08907, Hospitalet de LLobregat, Spain aut NATIONALLICENCE 700 1- Blanco Rosa Institut de Neuropatologia, Servei Anatomia Patològica, CIBERNED, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, carrer Feixa LLarga sn, 08907, Hospitalet de LLobregat, Spain aut NATIONALLICENCE 700 1- Dalfó Ester Institut de Neuropatologia, Servei Anatomia Patològica, CIBERNED, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, carrer Feixa LLarga sn, 08907, Hospitalet de LLobregat, Spain aut NATIONALLICENCE 700 1- Carmona Margarita Institut de Neuropatologia, Servei Anatomia Patològica, CIBERNED, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, carrer Feixa LLarga sn, 08907, Hospitalet de LLobregat, Spain aut NATIONALLICENCE 773 0- Journal of Neural Transmission Springer Vienna 118/5(2011-05-01), 821-839 0300-9564 118:5<821 2011 118 702 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer