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Pathomechanisms of depression in multiple system atrophy

  • Neurology and Preclinical Neurological Studies - Review Article
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Abstract

Multiple system atrophy (MSA) is a rapidly progressing neurodegenerative disorder of uncertain etiology that is characterized by various combinations of Parkinsonism, autonomic, cerebellar and motor dysfunctions, with poor prognosis. Little is known about modifiable factors, such as depression, that has negative effects on quality of life in MSA. Depression, with an estimated prevalence of about 43%, is among the most common neuropsychiatric disorders in MSA similar to other atypical Parkinsonian disorders, the frequency of which is associated with increased disease progression, disease severity and autonomic dysfunctions. Depression in MSA, like in Parkinson disease, has been related to a variety of pathogenic mechanisms associated with the underlying neurodegenerative process, such as involvement of serotonergic neuron groups in the brainstem, prefrontal cortical dysfunctions, and altered functional fronto-temporal-thalamic connectivities with disturbances of mood related and other essential resting-state brain networks. The pathophysiology and pathogenesis of depression in MSA, as in other degenerative movement disorders, are complex and deserve further elucidation as a basis for adequate treatment to improve the quality of life in this fatal disease.

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References

  • Aarsland D, Påhlhagen S, Ballard CG, Ehrt U, Svenningsson P (2011) Depression in Parkinson disease–epidemiology, mechanisms and management. Nat Rev Neurol 8:35–47

    Article  Google Scholar 

  • Almeida L, Ahmed B, Walz R, De Jesus S, Patterson A, Martinez-Ramirez D, Vaillancourt D, Bowers D, Ward H, Okun MS, McFarland NR (2017) Depressive symptoms are frequent in atypical parkinsonian disorders. Mov Disord Clin Pract 4:191–197

    Article  Google Scholar 

  • American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders. American Psychiatric Publishing, Washington, London

    Book  Google Scholar 

  • Balas M, Balash Y, Giladi N, Gurevich T (2010) Cognition in multiple system atrophy: neuropsychological profile and interaction with mood. J Neural Transm 117:369–375

    Article  Google Scholar 

  • Belvisi D, Berardelli I, Suppa A, Fabbrini A, Pasquini M, Pompili M, Fabbrini G (2018) Neuropsychiatric disturbances in atypical parkinsonian disorders. Neuropsychiatr Dis Treat 14:2643–2656

    Article  Google Scholar 

  • Benarroch EE, Schmeichel AM, Low PA, Parisi JE (2004) Involvement of medullary serotonergic groups in multiple system atrophy. Ann Neurol 55:418–422

    Article  Google Scholar 

  • Benarroch EE, Schmeichel AM, Sandroni P, Parisi JE, Low PA (2007) Rostral raphe involvement in Lewy body dementia and multiple system atrophy. Acta Neuropathol 114:213–220

    Article  CAS  Google Scholar 

  • Benrud-Larson LM, Sandroni P, Schrag A, Low PA (2005) Depressive symptoms and life satisfaction in patients with multiple system atrophy. Mov Disord 20:951–957

    Article  Google Scholar 

  • Bower SM, Weigand SD, Ali F, Clark HM, Botha H, Stierwalt JA, Whitwell JL, Josephs KA (2021) Depression and apathy across different variants of progressive supranuclear palsy. Mov Disord Clin Pract 9:212–217

    Article  Google Scholar 

  • Caso F, Canu E, Lukic MJ, Petrovic IN, Fontana A, Nikolic I, Kostic VS, Filippi M, Agosta F (2020) Cognitive impairment and structural brain damage in multiple system atrophy-parkinsonian variant. J Neurol 267:87–94

    Article  Google Scholar 

  • Ceponiene R, Edland SD, Reid TN, Rizaiza a Al, Litvan I (2016) Neuropsychiatric symptoms and their impact on quality of life in multiple system atrophy. Cogent Psychol. https://doi.org/10.1080/23311908.23312015.21131476

    Article  Google Scholar 

  • Chendo I, Silva C, Duarte GS, Prada L, Vian J, Quintão A, Voon V, Ferreira JJ (2022) Frequency of depressive disorders in Parkinson’s disease: a systematic review and meta-analysis. J Parkinsons Dis 12:1409–1418

    Article  CAS  Google Scholar 

  • Cuoco S, Picillo M, Cappiello A, Carotenuto I, Erro R, Russillo MC, Abate F, Volpe G, Squillante M, Cozzolino A, Cicarelli G, Santangelo G, Barone P, Pellecchia MT (2020) Effects of gender on cognitive and behavioral manifestations in multiple system atrophy. J Neural Transm 127:925–934

    Article  Google Scholar 

  • Dash SK, Stezin A, Takalkar T, George L, Kamble NL, Netravathi M, Yadav R, Kumar KJ, Ingalhalikar M, Saini J, Pal PK (2019) Abnormalities of white and grey matter in early multiple system atrophy: comparison of parkinsonian and cerebellar variants. Eur Radiol 29:716–724

    Article  Google Scholar 

  • Du JJ, Wang T, Huang P, Cui S, Gao C, Lin Y, Fu R, Zhou H, Chen S (2018) Clinical characteristics and quality of life in Chinese patients with multiple system atrophy. Brain Behav 8:e01135

    Article  Google Scholar 

  • Eschlböck S, Delazer M, Krismer F, Bodner T, Fanciulli A, Heim B, Heras Garvin A, Kaindlstorfer C, Karner E, Mair K, Rabensteiner C, Raccagni C, Seppi K, Poewe W, Wenning GK (2020) Cognition in multiple system atrophy: a single-center cohort study. Ann Clin Transl Neurol 7:219–228

    Article  Google Scholar 

  • Fanciulli A, Wenning GK (2015) Multiple-system atrophy. N Engl J Med 372:249–263

    Article  Google Scholar 

  • Fetoni V, Soliveri P, Monza D, Testa D, Girotti F (1999) Affective symptoms in multiple system atrophy and Parkinson’s disease: response to levodopa therapy. J Neurol Neurosurg Psychiatry 66:541–544

    Article  CAS  Google Scholar 

  • Flavell J, Nestor PJ (2022) A systematic review of apathy and depression in progressive supranuclear palsy. J Geriatr Psychiatry Neurol 35:280–292

    Article  Google Scholar 

  • Friess E, Kuempfel T, Modell S, Winkelmann J, Holsboer F, Ising M, Trenkwalder C (2006) Paroxetine treatment improves motor symptoms in patients with multiple system atrophy. Parkinsonism Relat Disord 12:432–437

    Article  Google Scholar 

  • Frisina PG, Haroutunian V, Libow LS (2009) The neuropathological basis for depression in Parkinson’s disease. Parkinsonism Relat Disord 15:144–148

    Article  Google Scholar 

  • Gill CE, Khurana RK, Hibler RJ (1999) Occurrence of depressive symptoms in Shy-Drager syndrome. Clin Auton Res 9:1–4

    Article  CAS  Google Scholar 

  • Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670–676

    Article  CAS  Google Scholar 

  • Hanganu A, Bruneau MA, Degroot C, Bedetti C, Mejia-Constain B, Lafontaine AL, Chouinard S, Monchi O (2017) Depressive symptoms in Parkinson’s disease correlate with cortical atrophy over time. Brain Cogn 111:127–133

    Article  Google Scholar 

  • Herting B, Beuthien-Baumann B, Pöttrich K, Donix M, Triemer A, Lampe JB, von Kummer R, Herholz K, Reichmann H, Holthoff VA (2007) Prefrontal cortex dysfunction and depression in atypical parkinsonian syndromes. Mov Disord 22:490–497

    Article  Google Scholar 

  • Huang P, Guan X, Guo T, Zeng Q, Xuan M, Gu Q, Xu X, Zhou C, Wu J, Zhang M (2020) Damaged insula network contributes to depression in Parkinson’s disease. Front Psychiatry 11:119

    Article  Google Scholar 

  • Jecmenica-Lukic M, Petrovic IN, Pekmezovic T, Tomic A, Stankovic I, Svetel M, Kostic VS (2021) The profile and evolution of neuropsychiatric symptoms in multiple system atrophy: self- and caregiver report. J Neuropsychiatry Clin Neurosci 33:124–131

    Article  Google Scholar 

  • Jellinger KA (2018) Multiple system atrophy: an oligodendroglioneural synucleinopathy. J Alzheimers Dis 62:1141–1179

    Article  CAS  Google Scholar 

  • Jellinger KA (2022) Heterogeneity of multiple system atrophy: an update. Biomedicines 10:599

    Article  CAS  Google Scholar 

  • Kao AW, Racine CA, Quitania LC, Kramer JH, Christine CW, Miller BL (2009) Cognitive and neuropsychiatric profile of the synucleinopathies: Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. Alzheimer Dis Assoc Disord 23:365–370

    Article  Google Scholar 

  • Kawahara Y, Ikeda Y, Deguchi K, Kurata T, Hishikawa N, Sato K, Kono S, Yunoki T, Omote Y, Yamashita T, Abe K (2015) Simultaneous assessment of cognitive and affective functions in multiple system atrophy and cortical cerebellar atrophy in relation to computerized touch-panel screening tests. J Neurol Sci 351:24–30

    Article  Google Scholar 

  • Kawai Y, Suenaga M, Takeda A, Ito M, Watanabe H, Tanaka F, Kato K, Fukatsu H, Naganawa S, Kato T, Ito K, Sobue G (2008) Cognitive impairments in multiple system atrophy: MSA-C vs MSA-P. Neurology 70:1390–1396

    Article  CAS  Google Scholar 

  • Kiely AP, Asi YT, Kara E, Limousin P, Ling H, Lewis P, Proukakis C, Quinn N, Lees AJ, Hardy J, Revesz T, Houlden H, Holton JL (2013) a-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy? Acta Neuropathol 125:753–769

    Article  CAS  Google Scholar 

  • Köllensperger M, Geser F, Ndayisaba JP, Boesch S, Seppi K, Ostergaard K, Dupont E, Cardozo A, Tolosa E, Abele M, Klockgether T, Yekhlef F, Tison F, Daniels C, Deuschl G, Coelho M, Sampaio C, Bozi M, Quinn N, Schrag A, Mathias CJ, Fowler C, Nilsson CF, Widner H, Schimke N, Oertel W, Del Sorbo F, Albanese A, Pellecchia MT, Barone P, Djaldetti R, Colosimo C, Meco G, Gonzalez-Mandly A, Berciano J, Gurevich T, Giladi N, Galitzky M, Rascol O, Kamm C, Gasser T, Siebert U, Poewe W, Wenning GK (2010) Presentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry. Mov Disord 25:2604–2612

    Article  Google Scholar 

  • Kostic VS, Filippi M (2011) Neuroanatomical correlates of depression and apathy in Parkinson’s disease: magnetic resonance imaging studies. J Neurol Sci 310:61–63

    Article  Google Scholar 

  • Kwentus JA, Auth TL, Foy JL (1984) Shy-Drager syndrome presenting as depression: case report. J Clin Psychiatry 45:137–139

    CAS  Google Scholar 

  • Liao H, Cai S, Shen Q, Fan J, Wang T, Zi Y, Mao Z, Situ W, Liu J, Zou T, Yi J, Zhu X, Tan C (2021) Networks are associated with depression in patients with Parkinson’s disease: a resting-state imaging study. Front Neurosci 14:573538

    Article  Google Scholar 

  • Lv Q, Pan Y, Chen X, Wei J, Wang W, Zhang H, Wan J, Li S, Zhuang Y, Yang B, Ma D, Ren D, Zhao Z (2022) Depression in multiple system atrophy: views on pathological, clinical and imaging aspects. Front Psychiatry 13:980371

    Article  Google Scholar 

  • Maillet A, Météreau E, Tremblay L, Favre E, Klinger H, Lhommée E, Le Bars D, Castrioto A, Prange S, Sgambato V, Broussolle E, Krack P, Thobois S (2021) Serotonergic and dopaminergic lesions underlying parkinsonian neuropsychiatric signs. Mov Disord 36:2888–2900

    Article  CAS  Google Scholar 

  • Martinez J, Palma JA, Norcliffe-Kaufmann L, Garakani A, Kaufmann H (2020) Impact of depressive symptoms on self-perceived severity of autonomic dysfunction in multiple system atrophy: relevance for patient-reported outcomes in clinical trials. Clin Auton Res 30:215–221

    Article  Google Scholar 

  • Obiora O, McCormick LM, Karim Y, Gonzales P, Beeghly J (2012) Maintenance electroconvulsive therapy in a patient with multiple system atrophy and bipolar disorder. J ECT 28:e1-2

    Article  Google Scholar 

  • Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H, Kilford L, Healy DG, Wood NW, Lees AJ, Holton JL, Revesz T (2004) The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 127:2657–2671

    Article  Google Scholar 

  • Pilo L, Ring H, Quinn N, Trimble M (1996) Depression in multiple system atrophy and in idiopathic Parkinson’s disease: a pilot comparative study. Biol Psychiatry 39:803–807

    Article  CAS  Google Scholar 

  • Pink A, Przybelski SA, Krell-Roesch J, Stokin GB, Roberts RO, Mielke MM, Knopman DS, Jack CR, Petersen RC, Geda YE (2017) Cortical thickness and depressive symptoms in cognitively normal individuals: the Mayo Clinic Study of Aging. J Alzheimers Dis 58:1273–1281

    Article  CAS  Google Scholar 

  • Prange S, Klinger H, Laurencin C, Danaila T, Thobois S (2022) Depression in patients with Parkinson’s disease: current understanding of its neurobiology and implications for treatment. Drugs Aging 39:417–439

    Article  CAS  Google Scholar 

  • Rascol O, Cochen de Cock V, Pavy-Le Traon A, Foubert-Samier A, Thalamas C, Sommet A, Rousseau V, Perez-Lloret S, Fabbri M, Azulay JP, Corvol JC, Couratier P, Damier P, Defebvre L, Durif F, Geny C, Houeto JL, Remy P, Tranchant C, Verin M, Tison F, Meissner WG (2021) Fluoxetine for the symptomatic treatment of multiple system atrophy: The MSA-FLUO Trial. Mov Disord 36:1704–1711

    Article  CAS  Google Scholar 

  • Roane DM, Rogers JD, Helew L, Zarate J (2000) Electroconvulsive therapy for elderly patients with multiple system atrophy: a case series. Am J Geriatr Psychiatry 8:171–174

    Article  CAS  Google Scholar 

  • Rohrer G, Höglinger GU, Levin J (2018) Symptomatic therapy of multiple system atrophy. Auton Neurosci 211:26–30

    Article  Google Scholar 

  • Santangelo G, Cuoco S, Picillo M, Erro R, Squillante M, Volpe G, Cozzolino A, Cicarelli G, Barone P, Pellecchia MT (2020) Evolution of neuropsychological profile in motor subtypes of multiple system atrophy. Parkinsonism Relat Disord 70:67–73

    Article  Google Scholar 

  • Schrag A, Geser F, Stampfer-Kountchev M, Seppi K, Sawires M, Köllensperger M, Scherfler C, Quinn N, Pellecchia MT, Barone P, Del Sorbo F, Albanese A, Ostergaard K, Dupont E, Cardozo A, Tolosa E, Nilsson CF, Widner H, Lindvall O, Giladi N, Gurevich T, Daniels C, Deuschl G, Coelho M, Sampaio C, Abele M, Klockgether T, Schimke N, Eggert KM, Oertel W, Djaldetti R, Colosimo C, Meco G, Poewe W, Wenning GK (2006) Health-related quality of life in multiple system atrophy. Mov Disord 21:809–815

    Article  Google Scholar 

  • Schrag A, Sheikh S, Quinn NP, Lees AJ, Selai C, Mathias C, Litvan I, Lang AE, Bower JH, Burn DJ, Low P, Jahanshahi M (2010) A comparison of depression, anxiety, and health status in patients with progressive supranuclear palsy and multiple system atrophy. Mov Disord 25:1077–1081

    Article  Google Scholar 

  • Schrag A, Bohlken J, Kostev K (2022) Pre-diagnostic presentations of multiple system atrophy case control study in a primary care dataset. Parkinsonism Relat Disord 99:101–104

    Article  Google Scholar 

  • Shen Q, Liu Y, Guo J, Zhang H, Xiang Y, Liao H, Cai S, Zhou B, Wang M, Liu S, Yi J, Zhang Z, Tan C (2022) Impaired white matter microstructure associated with severe depressive symptoms in patients with PD. Brain Imaging Behav 16:169–175

    Article  Google Scholar 

  • Shioda K, Nisijima K, Kato S (2006) Electroconvulsive therapy for the treatment of multiple system atrophy with major depression. Gen Hosp Psychiatry 28:81–83

    Article  Google Scholar 

  • Siri C, Duerr S, Canesi M, Delazer M, Esselink R, Bloem BR, Gurevich T, Balas M, Giladi N, Santacruz P, Marti F, Tolosa E, Rubino A, Meco G, Poewe W, Pezzoli G, Wenning G, Antonini A (2013) A cross-sectional multicenter study of cognitive and behavioural features in multiple system atrophy patients of the parkinsonian and cerebellar type. J Neural Transm 120:613–618

    Article  CAS  Google Scholar 

  • Song DD, Yu YX, Dong QW, Zhang HL, Liu JG, Liu Q, Yu J, Qi XK (2013) Assessment of cognitive function, emotions and activities of daily living in patients with multiple system atrophy. Zhonghua Yi Xue Za Zhi 93:1948–1951

    Google Scholar 

  • Sonoda Y, Yamanaka Y, Sawano S, Komada R, Kugo M, Kitamura A, Ogawa N, Yamakawa I, Kim H, Sanada M, Imai S, Urushitani M (2021) Amelioration of motor and nonmotor symptoms in cortical cerebellar atrophy and multiple system atrophy-cerebellar type by inpatient rehabilitation: a retrospective study. Int J Rehabil Res 44:104–109

    Article  Google Scholar 

  • Steinbusch HWM, Dolatkhah MA, Hopkins DA (2021) Anatomical and neurochemical organization of the serotonergic system in the mammalian brain and in particular the involvement of the dorsal raphe nucleus in relation to neurological diseases. Prog Brain Res 261:41–81

    Article  Google Scholar 

  • Torny F, Lacoste M, Videaud H, Chouly M, Parveau MC, Couratier P (2009) Comparison of quality of life in multiple system atrophy and Parkinson’s disease. Rev Neurol (paris) 165:911–915

    Article  CAS  Google Scholar 

  • Tsai P, Gopalakrishna G (2022) Mood disorders in Parkinson’s disease. In: Gálvez-Jiménez N, Korczyn A, Lugo-Sanchez R (eds) Non-motor Parkinson’s disease. Cambridge University Press Cambridge, Cambridge, pp 91–98. https://doi.org/10.1017/9781009039291.9781009039010

    Chapter  Google Scholar 

  • Wang H, Tang X, Zhou J, Xu Y (2022) Excessive daytime sleepiness is associated with non-motor symptoms of multiple system atrophy: a cross-sectional study in China. Front Neurol 12:798771

    Article  Google Scholar 

  • Wang N, Edmiston EK, Luo X, Yang H, Chang M, Wang F, Fan G (2017) Comparing abnormalities of amplitude of low-frequency fluctuations in multiple system atrophy and idiopathic Parkinson’s disease measured with resting-state fMRI. Psychiatry Res Neuroimaging 269:73–81

    Article  Google Scholar 

  • Wei L, Hu X, Yuan Y, Liu W, Chen H (2018) Abnormal ventral tegmental area-anterior cingulate cortex connectivity in Parkinson’s disease with depression. Behav Brain Res 347:132–139

    Article  Google Scholar 

  • Weintraub D, Aarsland D, Chaudhuri KR, Dobkin RD, Leentjens AF, Rodriguez-Violante M, Schrag A (2022) The neuropsychiatry of Parkinson’s disease: advances and challenges. Lancet Neurol 21:89–102

    Article  Google Scholar 

  • Winter Y, Spottke AE, Stamelou M, Cabanel N, Eggert K, Höglinger GU, Sixel-Doering F, Herting B, Klockgether T, Reichmann H, Oertel WH, Dodel R (2011) Health-related quality of life in multiple system atrophy and progressive supranuclear palsy. Neurodegener Dis 8:438–446

    Article  Google Scholar 

  • Yang HG, Liu WV, Wen Z, Hu LH, Fan GG, Zha YF (2022) Altered voxel-level whole-brain functional connectivity in multiple system atrophy patients with depression symptoms. BMC Psychiatry 22:279

    Article  Google Scholar 

  • Zhang LY, Cao B, Zou YT, Wei QQ, Ou RW, Zhao B, Wu Y, Shang HF (2018) Depression and anxiety in multiple system atrophy. Acta Neurol Scand 137:33–37

    Article  Google Scholar 

  • Zhang L, Cao B, Zou Y, Wei QQ, Ou R, Zhao B, Yang J, Wu Y, Shang H (2019) Frontal lobe function, behavioral changes and quality of life in patients with multiple system atrophy. Restor Neurol Neurosci 37:11–19

    CAS  Google Scholar 

  • Zhao B, Liu H, Li H, Shang X (2018) Abnormal functional connectivity of the amygdala is associated with depressive symptoms in patients with multiple system atrophy. Neuropsychiatr Dis Treat 14:3133–3142

    Article  CAS  Google Scholar 

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Acknowledgements

The author thanks Mr. E. Mitter-Ferstl, PhD, for secretarial and editorial work.

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The study was funded by the Society for the Promotion of Research in Experimental Neurology, Vienna, Austria.

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  1. Institute of Clinical Neurobiology, Alberichgasse 5/13, 1150, Vienna, Austria

    Kurt A. Jellinger

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Jellinger, K.A. Pathomechanisms of depression in multiple system atrophy. J Neural Transm 130, 1–6 (2023). https://doi.org/10.1007/s00702-022-02560-y

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