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Chapter 4 - Neuropathology of Non-Motor Parkinson’s Disease Symptoms

Published online by Cambridge University Press:  05 March 2022

By
Helmut Heinsen  and
Lea Tenenholz Grinberg
Edited by
Néstor Gálvez-Jiménez ,
Amos D. Korczyn  and
Ramón Lugo-Sanchez
Néstor Gálvez-Jiménez
Affiliation:
Florida International University
Amos D. Korczyn
Affiliation:
Tel-Aviv University
Ramón Lugo-Sanchez
Affiliation:
Cleveland Clinic
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Summary

Lewy body disease, an α-synucleinopathy, is the neuropathological counterpart of idiopathic Parkinson’s disease and one of the most frequent neurodegenerative diseases in humans [1]. Parkinson’s disease features compelling motor symptoms. Parkinson summarized these symptoms under the mixed Greek-Latin term paralysis agitans (shaking palsy) [2], and for decades, these motor symptoms described by Parkinson remained the most studied features of Lewy body disease.

However, autonomic dysfunctions and non-motor symptoms associated with Lewy body disease are frequent and often pre-date the onset of motor diseases [3]. Autonomic dysfunctions comprise constipation, bowel dysfunction, seborrheic face, dysphagia, dysarthria, impotence, urinary frequency, bladder dysfunction, orthostatic hypotension, and increased sweating. Other non-motor symptoms include sleep disorders (REM behavior disorder, vivid dreams, daytime drowsiness, sleep fragmentation cognitive impairment, bradyphrenia, tip-of-the-tongue (word-finding) phenomenon, depression, apathy, anhedonia, fatigue, behavioral and psychiatric problems, sensory symptoms including anosmia, ageusia, pain (shoulder, back), and paresthesias [4].

Type
Chapter
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Non-motor Parkinson's Disease , pp. 35 - 45
Publisher: Cambridge University Press
Print publication year: 2022

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References

Ascherio, A, Schwarzschild, MA. The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol 2016; 15 (12): 1255–1270.Google Scholar
Parkinson, J. An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci 2002; 14 (2): 223–236; discussion 222.CrossRefGoogle ScholarPubMed
Obeso, JA, Stamelou, M, Goetz, CG, et al. Past, present, and future of Parkinson’s disease: a special essay on the 200th Anniversary of the Shaking Palsy. Mov Disord 2017; 32 (9): 1264–1310.CrossRefGoogle ScholarPubMed
Jellinger, KA. Parkinson’s disease. In Dickson, DW and Weller, RO (eds.). Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. Wiley Blackwell; 2011, 194–224.CrossRefGoogle Scholar
Hely, MA, Reid, WG, Adena, MA, et al. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 2008; 23 (6): 837–844.CrossRefGoogle Scholar
Lim, SY, Lang, AE. The nonmotor symptoms of Parkinson’s disease: an overview. Mov Disord 2010; 25 (3): S123–S130.CrossRefGoogle Scholar
Martinez-Martin, P, Rodriguez-Blazquez, C, Kurtis, MM, et al. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’s disease. Mov Disord 2011; 26 (3): 399–406.Google Scholar
Rajput, AH, Voll, A, Rajput, ML, et al. Course in Parkinson disease subtypes: a 39-year clinicopathologic study. Neurology 2009; 73 (3): 206–212.Google Scholar
Selikhova, M, Williams, DR, Kempster, PA, et al. A clinico-pathological study of subtypes in Parkinson’s disease. Brain 2009; 132 (Pt 11): 2947–2957.CrossRefGoogle ScholarPubMed
Lang, AE, Lozano, AM. Parkinson’s disease. First of two parts. N Engl J Med 1998; 339 (15): 1044–1053.Google Scholar
Dickson, DW, Braak H, , Duda, JE, et al. Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol 2009; 8(12): 1150–1157.CrossRefGoogle ScholarPubMed
Lewy, FH. Zur pathologischen Anatomie der Paralysis agitans. Deutsche Zeitschrift für Nervenheilkunde 1914; 50 (1–4 Siebente Jahresversammlung der Gesellschaft Deutscher Nervenärzte in: Breslau am 29. September bis 1. Oktober 1913): 50–55.Google Scholar
Wakabayashi, K, Tanji K, , Odagiri, S, et al. The Lewy body in Parkinson’s disease and related neurodegenerative disorders. Mol Neurobiol 2013; 47 (2): 495–508.Google Scholar
Flagmeier, P, Meisl G, , Vendruscolo, M, et al. Mutations associated with familial Parkinson’s disease alter the initiation and amplification steps of α-synuclein aggregation. Proc Natl Acad Sci USA 2016; 113 (37): 10328–10333.CrossRefGoogle ScholarPubMed
Burre, J. The synaptic function of alpha-synuclein. J Parkinson’s Dis 2015; 5(4): 699–713.CrossRefGoogle ScholarPubMed
Erskine, D, Patterson L, , Alexandris, A, et al. Regional levels of physiological α-synuclein are directly associated with Lewy body pathology. Acta Neuropathol 2018; 135 (1): 153–154.CrossRefGoogle ScholarPubMed
Peelaerts, W, Bousset, L, Van der Perren, A, et al. Alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 2015; 522 (7556): 340–344.CrossRefGoogle ScholarPubMed
Villar-Piqué, A, Lopes, da Fonseca T, , Sant’Anna, R, et al. Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity. Proc Natl Acad Sci USA 2016; 113 (42): E6506–E6515.Google Scholar
Bieri, G, Gitler, AD, Brahic, M. Internalization, axonal transport and release of fibrillar forms of alpha-synuclein. Neurobiol Dis 2018; 109 (B): 219–225.Google Scholar
Melki, R. How the shapes of seeds can influence pathology. Neurobiol Dis 2018; 109 (Pt B): 201–208.CrossRefGoogle ScholarPubMed
Peelaerts, W, Bousset L, , Baekelandt V, , Melki, R. α-Synuclein strains and seeding in Parkinson’s disease, incidental Lewy body disease, dementia with Lewy bodies and multiple system atrophy: similarities and differences. Cell Tissue Res 2018; 373 (1): 195–212.Google Scholar
Osterberg, VR, Spinelli KJ, , Weston, LJ, et al. Progressive aggregation of alpha-synuclein and selective degeneration of Lewy inclusion-bearing neurons in a mouse model of parkinsonism. Cell Rep 2015; 10 (8): 1252–1260.Google Scholar
Borghammer, P. How does parkinson’s disease begin? Perspectives on neuroanatomical pathways, prions, and histology. Mov Disord 2018; 33 (1): 48–57.CrossRefGoogle ScholarPubMed
Vargas, JY, Grudina C, , Zurzolo C., The prion-like spreading of α-synuclein: from in vitro to in vivo models of Parkinson’s disease. Ageing Res Rev 2019; 50: 89–101.Google Scholar
Markesbery, WR, Jicha GA, , Liu H, , Schmitt FA., Lewy body pathology in normal elderly subjects. J Neuropathol Exp Neurol 2009; 68 (7): 816–822.Google Scholar
Greffard, S, Verny M, , Bonnet, AM, et al. A stable proportion of Lewy body bearing neurons in the substantia nigra suggests a model in which the Lewy body causes neuronal death. Neurobiol Aging 2010; 31 (1): 99–103.CrossRefGoogle Scholar
Surmeier, DJ, Obeso JA, , Halliday GM., Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 2017; 18 (2): 101–113.Google Scholar
McKeith, IG, Dickson DW, , Lowe, J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005; 65 (12): 1863–1872.CrossRefGoogle ScholarPubMed
Beach, TG, White CL, , Hamilton, RL, et al. Evaluation of alpha-synuclein immunohistochemical methods used by invited experts. Acta Neuropathol 2008; 116 (3): 277–288.Google Scholar
Duda, JE. Olfactory system pathology as a model of Lewy neurodegenerative disease. J Neurolog Sci 2010; 289 (1–2): 49–54.CrossRefGoogle Scholar
Kanazawa, T, Adachi, E, Orimo, S, et al. Pale neurites, premature alpha-synuclein aggregates with centripetal extension from axon collaterals. Brain Pathol 2012; 22 (1): 67–78.Google Scholar
Colom-Cadena, M, Pegueroles J, , Herrmann, AG, et al. Synaptic phosphorylated α-synuclein in dementia with Lewy bodies. Brain 2017; 140 (12): 3204–3214.Google Scholar
Chartier, S, Duyckaerts C., Is Lewy pathology in the human nervous system chiefly an indicator of neuronal protection or of toxicity? Cell Tissue Res 2018; 373 (1): 149–160.Google Scholar
Seeley, WW, Crawford RK, , Zhou J, , Miller BL, , Greicius MD., Neurodegenerative diseases target large-scale human brain networks. Neuron 2009; 62 (1): 42–52.CrossRefGoogle ScholarPubMed
Braak, H, Del Tredici K, , Rüb, U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24 (2): 197–211.Google Scholar
Kosaka, K, Tsuchiya K, , Yoshimura M., Lewy body disease with and without dementia: a clinicopathological study of 35 cases. Clin Neuropathol 1988; 7 (6): 299–305.Google ScholarPubMed
Braak, H, Rüb U, , Gai WP, , Del Tredici K., Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 2003; 110 (5): 517–536.Google Scholar
Hawkes, CH, Del Tredici, K, Braak H., Parkinson’s disease: a dual-hit hypothesis. Neuropathol Applied Neurobiol 2007; 33 (6): 599–614.Google Scholar
Braak, H, Del Tredici, K. Neuroanatomy and pathology of sporadic Parkinson’s disease. Adv Anatomy Embryol Cell Biol 2009; 201: 1–119.Google ScholarPubMed
Oyanagi, K, Wakabayashi K, , Ohama, E, et al. Lewy bodies in the lower sacral parasympathetic neurons of a patient with Parkinson’s disease. Acta Neuropathol 1990; 80 (5): 558–559.Google Scholar
Hishikawa, N, Hashizumeb Y, , Yoshida M, , Sobue G., Clinical and neuropathological correlates of Lewy body disease. Acta Neuropathol 2003; 105 (4): 341–350.Google Scholar
Bloch, A, Probst A, , Bissig H, et al. Alpha-synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol Applied Neurobiol 2006; 32 (3): 284–295.CrossRefGoogle ScholarPubMed
Klos, KJ, Ahlskog JE, , Josephs, KA, et al. Alpha-synuclein pathology in the spinal cords of neurologically asymptomatic aged individuals. Neurology 2006; 66 (7): 1100–1102.Google Scholar
Beach, TG, Adler CH, , Sue, LI, et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 2010; 119 (6): 689–702.CrossRefGoogle ScholarPubMed
Oinas, M, Paetau A, , Myllykangas, L, et al. Alpha-synuclein pathology in the spinal cord autonomic nuclei associates with alpha-synuclein pathology in the brain: a population-based Vantaa 85+study. Acta Neuropathol 2010; 119 (6): 715–722.Google Scholar
Del Tredici, K, Braak H., Spinal cord lesions in sporadic Parkinson’s disease. Acta Neuropathol 2012; 124 (5): 643–664.Google Scholar
Tamura, T, Yoshida M, , Hashizume, Y, Sobue G., Lewy body-related α-synucleinopathy in the spinal cord of cases with incidental Lewy body disease. Neuropathology 2012; 32 (1): 13–22.Google Scholar
Jellinger, KA. Is Braak staging valid for all types of Parkinson’s disease? J Neural Transm 2019; 126 (4): 423–431.Google Scholar
Orimo, S, Ghebremedhin, E, Gelpi E., Peripheral and central autonomic nervous system: does the sympathetic or parasympathetic nervous system bear the brunt of the pathology during the course of sporadic PD? Cell Tissue Res 2018; 373 (1): 267–286.Google Scholar
Wakabayashi, K, Takahashi, H. The intermediolateral nucleus and Clarke’s column in Parkinson’s disease. Acta Neuropathol 1997; 94: 287–289.CrossRefGoogle ScholarPubMed
Krämer, HH, Lautenschläger G, , de Azevedo, M, et al. Reduced central sympathetic activity in Parkinson’s disease. Brain Behav 2019; 9 (12): e01463.Google Scholar
Orimo, S, Oka T, , Miura, H, et al. Sympathetic cardiac denervation in Parkinson’s disease and pure autonomic failure but not in multiple system atrophy. J Neurol Neurosurg Psychiatry 2002; 73 (6): 776–777.Google Scholar
Orimo, S, Takahashi A, , Uchihara, T, et al. Degeneration of cardiac sympathetic nerve begins in the early disease process of Parkinson’s disease. Brain Pathol 2007; 17 (1): 24–30.Google Scholar
Cersosimo, MG, Benarroch EE., Autonomic involvement in Parkinson’s disease: pathology, pathophysiology, clinical features and possible peripheral biomarkers. J Neurolog Sci 2012; 313 (1–2): 57–63.Google Scholar
Braune, S, Reinhardt, M, Schnitzer, R, et al. Cardiac uptake of [123I]MIBG separates Parkinson’s disease from multiple system atrophy. Neurology 1999; 53 (5): 1020–1025.Google Scholar
Travagli, RA, Hermann GE, , Browning KN, , Rogers, RC. Brainstem circuits regulating gastric function. Ann Rev Physiol 2006; 68: 279–305.CrossRefGoogle ScholarPubMed
Quigley, EMM. Gastrointestinal dysfunction in Parkinson’s disease. Semin Neurol 1996; 16 (03): 245–250.Google Scholar
Adler, CH. Nonmotor complications in Parkinson’s disease. Mov Disord 2005; 20 (Suppl 11): S23–S29.CrossRefGoogle ScholarPubMed
Jost, WH. Gastrointestinal dysfunction in Parkinson’s disease. J Neurolog Sci 2010; 289 (1–2): 69–73.Google Scholar
Lebouvier, T, Coron E, , Chaumette, T, et al. Routine colonic biopsies as a new tool to study the enteric nervous system in living patients. Neurogastroenterol Motility 2010; 22 (1): e11–e14.CrossRefGoogle Scholar
Derkinderen, P, Rouaud T, , Lebouvier, T, et al. Parkinson disease: the enteric nervous system spills its guts. Neurology 2011; 77 (19): 1761–1767.Google Scholar
Kaufmann, H, Nahm K, , Purohit, D, Wolfe D., Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology 2004; 63 (6): 1093–1095.Google Scholar
Beach, TG, Adler CH, , Dugger, BN, et al. Submandibular gland biopsy for the diagnosis of Parkinson disease. J Neuropathol Exp Neurol 2013; 72 (2): 130–136.Google Scholar
Ruffmann, C, Parkkinen L., Gut feelings about -synuclein in gastrointestinal biopsies: biomarker in the making? Mov Disord 2016; 31 (2): 193–202.Google Scholar
Taber, KH. Hurley RA., Volume transmission in the brain: beyond the synapse. J Neuropsychiatry Clin Neurosci 2014; 26 (1): iv–4.CrossRefGoogle ScholarPubMed
Braak, H, Sastre M, , Bohl, JRE, et al. Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 2007; 113 (4): 421–429.Google Scholar
Nieuwenhuys, R, Voogd, J, van Huijzen C., The Human Central Nervous System. Springer; 2008.CrossRefGoogle Scholar
Iranzo, A. The REM sleep circuit and how its impairment leads to REM sleep behavior disorder. Cell Tissue Res 2018; 373 (1): 245–266.CrossRefGoogle ScholarPubMed
Fronczek, R, Overeem S, , Lee, SYY, et al. Hypocretin (orexin) loss in Parkinson’s disease. Brain 2007; 130 (Pt 6): 1577–1585.Google Scholar
Ferman, TJ, Boeve BF, , Smith, GE, et al. Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies. Neurology 2011; 77 (9): 875–882.CrossRefGoogle ScholarPubMed
Eser, RA, Ehrenberg AJ, , Petersen, C, et al. Selective vulnerability of brainstem nuclei in distinct tauopathies: a postmortem study. J Neuropathol Exp Neurol 2018; 77 (2): 149–161.Google Scholar
Boeve, BF, St Louis EK, , Kantarci K., Neuromelanin-sensitive imaging in patients with idiopathic rapid eye movement sleep behaviour disorder. Brain 2016; 139 (Pt 4): 1005–1007.Google Scholar
Dauvilliers, Y, Schenck CH, , Postuma, RB, et al. REM sleep behaviour disorder. Nat Rev Dis Primers 2018; 4 (1): 19.Google Scholar
Grinberg, LT, Rueb U, , Alho AT, , Heinsen H., Brainstem pathology and non-motor symptoms in PD. J Neurolog Sci 2010; 289 (1–2): 81–88.Google Scholar
Remy, P, Doder M, , Lees, A, et al. Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 2005; 128 (Pt 6): 1314–1322.Google Scholar
Lian, TH, Guo P, , Zuo LJ, , et al. An investigation on the clinical features and neurochemical changes in Parkinson’s disease with depression. Front Psychiatry 2019; 9: 723.Google Scholar
O’Brien, JT, Holmes C, , Jones, M, et al. Clinical practice with anti-dementia drugs: a revised (third) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol 2017; 31 (2): 147–168.Google Scholar
Hershey, LA, Coleman-Jackson R., Pharmacological management of dementia with Lewy bodies. Drugs Aging 2019; 36 (4): 309–319.Google Scholar
Harding, AJ, Stimson E, , Henderson JM, , Halliday GM., Clinical correlates of selective pathology in the amygdala of patients with Parkinson’s disease. Brain 2002; 125: 2431–2445.Google Scholar
Liu, J, Heinsen H, , Grinberg, LT, et al. Pathoarchitectonics of the cerebral cortex in chorea-acanthocytosis and Huntington’s disease. Neuropathol Applied Neurobiol 2019; 45 (3): 230–243.Google Scholar
Adler, CH, Beach TG, , Zhang, N, et al. Unified staging system for Lewy body disorders: clinicopathologic correlations and comparison to Braak staging. J Neuropathol Exp Neurol 2019; 78 (10): 891–899.Google Scholar
Cersosimo, MG. Propagation of alpha-synuclein pathology from the olfactory bulb: possible role in the pathogenesis of dementia with Lewy bodies. Cell Tissue Res 2018; 373 (1): 233–243.Google Scholar
Steiner, JA, Quansah E, , Brundin P., The concept of alpha-synuclein as a prion-like protein: ten years after. Cell Tissue Res 2018; 373 (1): 161–173.Google Scholar
Tamgüney, G, Korczyn A., A critical review of the prion hypothesis of human synucleinopathies. Cell Tissue Res 2018; 373 (1): 213–220.Google Scholar
Seidel, K, Mahlke J, , Siswanto, S, et al. The brainstem pathologies of Parkinson’s disease and dementia with Lewy bodies. Brain Pathol 2015; 25 (2): 121–135.Google Scholar
Riederer, P, Jellinger KA, , Kolber, P, et al. Lateralisation in Parkinson disease. Cell Tissue Res 2018; 373 (1): 297–312.Google Scholar
Pakkenberg, B, Møller A, , Gundersen, HJG, et al. The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson’s disease estimated with an unbiased stereological method. J Neurol Neurosurg Psychiatry 1991; 54: 30–33.CrossRefGoogle ScholarPubMed
Rudow, G, O’Brien R, , Savonenko, AV, et al. Morphometry of the human substantia nigra in ageing and Parkinson’s disease. Acta Neuropathol 2008; 115 (4): 461–470.Google Scholar
Kempster, PA, Gibb WR, , Stern GM, , Lees AJ., Asymmetry of substantia nigra neuronal loss in Parkinson’s disease and its relevance to the mechanism of levodopa related motor fluctuations. J Neurol Neurosurg Psychiatry 1989; 52 (1): 72–76.Google Scholar
Di Lorenzo Alho, AT, Suemoto CK, , Polichiso, L, et al. Three-dimensional and stereological characterization of the human substantia nigra during aging. Brain Struct Funct 2016; 221 (7): 3393–3403.Google Scholar
Massari, VJ, Johnson TA, , Gatti PJ., Cardiotopic organization of the nucleus ambiguus? An anatomical and physiological analysis of neurons regulating atrioventricular conduction. Brain Res 1995; 679: 227–240.Google Scholar
Coon, EA, Cutsforth-Gregory JK, , Benarroch EE., Neuropathology of autonomic dysfunction in synucleinopathies. Mov Disord 2018; 33 (3): 349–358.CrossRefGoogle ScholarPubMed
Pauza, DH, Skripka, V, Pauziene, N, Stropus, R. Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart. Anat Rec 2000; 259 (4): 353–382.Google Scholar
Ghebremedhin, E, Del Tredici, K, Langston, JW, Braak, H. Diminished tyrosine hydroxylase immunoreactivity in the cardiac conduction system and myocardium in Parkinson’s disease: an anatomical study. Acta Neuropathol 2009; 118 (6): 777–784.Google Scholar

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