Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-745bb68f8f-b95js Total loading time: 0 Render date: 2025-01-09T11:35:04.564Z Has data issue: false hasContentIssue false

Chapter 4 - Neuropathological Overview of Neurodegenerative Disorders

from Section 1: - Basic Introduction

Published online by Cambridge University Press:  07 January 2025

By
Erik Ch. Wolters
Edited by
Erik Ch. Wolters  and
Christian R. Baumann
Erik Ch. Wolters
Affiliation:
Universität Zürich
Christian R. Baumann
Affiliation:
Universität Zürich
Get access

Summary

Neurodegenerative disorders are complex multisystem disorders mainly characterized by aggregations of misfolded proteins (such as misfolded amyloid-beta protein in Alzheimer’s disease) in select regions in the central, peripheral, and autonomic nervous systems. In this chapter the various proteinopathic neurodegenerative movement disorders will be dealt with: synucleinopathies, tauopathies, frontotemporal lobar degenerations with TAU, TAR DNA binding protein-43 (TDP), and/or fused in sarcoma (FUS) proteinopathies, polyglutamine CAG-repeat disorders, and misfolded prion proteins. Abnormal protein deposits can be visualized post mortem with immunohistochemical methods that define the diseases, allow the staging schemes, and establish correlations between neuropathologic and clinical phenotypes. As neurodegenerative disorders often display comorbidity, immunohistochemistry with antibody panels has to be performed to enable assessment of the specific protein aggregations in various regions.

Keywords

Neurodegenerationneuropathologic hallmarkssynucleinopathiestauopathiespolyglutamine disordersCAG repeat diseasesprion diseases.
Type
Chapter
Information
International Compendium of Movement Disorders , pp. 53 - 73
Publisher: Cambridge University Press
Print publication year: 2025

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Bloomingdale, P, Karelina, T, Ramakrishnan, V. Hallmarks of neurodegenerative disease: a systems pharmacology perspective. CPT Pharmacometrics Syst Pharmacol 2022;11:1399–13429.CrossRefGoogle ScholarPubMed
Hetz, C, Saxena, S. ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol 2017;13:477–491.CrossRefGoogle ScholarPubMed
Ransohoff, RM. How neuroinflammation contributes to neurodegeneration. Science 2016;353:777–783.CrossRefGoogle ScholarPubMed
Rubinsztein, DC, Marino, G, Kroemer, G. Autophagy and aging. Cell 2011;146:682–695.CrossRefGoogle ScholarPubMed
Braak, H, Del Tredici, K. Potential pathways of abnormal tau and alpha-synuclein dissemination in sporadic Alzheimer’s and Parkinson’s diseases. Cold Spring Harb Perspect Biol. 2016;8:a023630.CrossRefGoogle ScholarPubMed
Sies, H, Jones, DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020;21:363–383.CrossRefGoogle Scholar
Hetz, C, Saxena, S. ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol 2017;13:477–491.CrossRefGoogle ScholarPubMed
Cabral-Miranda, F, Hetz, C. ER stress and neurodegenerative disease: a cause or effect relationship? Curr Top Microbiol Immunol 2018;414:131–157.Google ScholarPubMed
Yu, J‐T, Xu, W, Tan, CC, et al. Evidence‐based prevention of Alzheimer’s disease: systematic review and meta‐analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry 2020;91:1201–1209.CrossRefGoogle ScholarPubMed
Willette, AA, Johnson, SC, Birdsill, AC, et al. Insulin resistance predicts brain amyloid deposition in late middle‐aged adults. Alzheimers Dement 2015;11:504–510.CrossRefGoogle ScholarPubMed
Hickman, S, Izzy, S, Sen, P, Morsett, L, El Khoury, J. Microglia in neurodegeneration. Nat Neurosci 2018;21:1359–1369.CrossRefGoogle ScholarPubMed
Sengupta, U, Kayed, R. Amyloid β, tau, and α-synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases. Progr Neurobiol 2022;214:102270.CrossRefGoogle ScholarPubMed
Moussaud, S, Jones, DR, Moussaud-Lamodière, EL, et al.Alpha-synuclein and tau: teammates in neurodegeneration? Mol Neurodegeneration 2014;9:43.CrossRefGoogle ScholarPubMed
Vasili, E, Dominguez-Meijide, A, Outeiro, TF. Spreading of α-synuclein and tau: a systematic comparison of the mechanisms involved. Front Mol Neurosci 2019;12:107.CrossRefGoogle Scholar
Adler, CH, Connor, DJ, Hentz, JG, et al. Incidental Lewy body disease: clinical comparison to a control cohort. Mov Disord 2010;25(5):642–646.CrossRefGoogle ScholarPubMed
Marras, C, Lang, A. Invited article: changing concepts in Parkinson disease: moving beyond the decade of the brain. Neurology 2008;70:1996–2003.CrossRefGoogle ScholarPubMed
Braak, H, Bohl, JR, Muller, CM, et al. The staging procedure for the inclusion body pathology associated with sporadic Parkinson’s disease reconsidered. Mov Disord 2006;21:2042–2051.CrossRefGoogle Scholar
Blauwendraat, C, Nalls, MA, Singleton, AB. The genetic architecture of Parkinson’s disease. Lancet Neurol 2020;19:170–178.CrossRefGoogle ScholarPubMed
Van de Berg, WDJ, Hepp, DA, Rozemuller, AJM. Neuropathology in movement disorders. In: Wolters, EC, Baumann, C, eds. Parkinson Disease and Other Movement Disorders. Motor Behavioural Disorders and Behavioural Motor Disorders. Amsterdam: VU University Press; 2014: 107–145.Google Scholar
Glass, M, Faull, RL, Dragunow, M. Loss of cannabinoid receptors in the substantia nigra in Huntington’s disease. Neuroscience 1993;56:523–527.CrossRefGoogle ScholarPubMed
Aarsland, D, Ballard, CG, Halliday, G. Are Parkinson’s disease with dementia and dementia with Lewy bodies the same entity? J Geriatr Psychiatry Neurol 2004;17:137–145.CrossRefGoogle ScholarPubMed
McKeith, IG, Dickson, DW, Lowe, J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863-1872.CrossRefGoogle ScholarPubMed
Spencer, BE, Jennings, RG, Fan, CC, Brewer, JB. Assessment of genetic risk for improved clinical–neuropathological correlations. Acta Neuropathol Commun 2020;8:160.CrossRefGoogle ScholarPubMed
Gilman, S, Wenning, GK, Low, PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71:670–676.CrossRefGoogle ScholarPubMed
Jellinger, KA, Lantos, PL. Papp–Lantos inclusions and the pathogenesis of multiple system atrophy: an update. Acta Neuropathol 2010;119:657–667.CrossRefGoogle ScholarPubMed
Spillantini, MG, Goedert, M. Tau pathology and neurodegeneration. Lancet Neurol 2013;12:609–622.CrossRefGoogle ScholarPubMed
Cowan, CM, Mudher, A. Are tau aggregates toxic or protective in tauopathies? Front Neurol 2013;4:114.CrossRefGoogle ScholarPubMed
Dickson, DW, Rademakers, R, Hutton, ML. Progressive supranuclear palsy: pathology and genetics. Brain Pathol 2007;17:74–82.CrossRefGoogle ScholarPubMed
Williams, DR, Holton, JL, Strand, C, et al. Pathological tau burden and distribution distinguishes progressive supranuclear palsy–parkinsonism from Richardson’s syndrome. Brain 2007;130:1566–1576.CrossRefGoogle ScholarPubMed
Chung, EJ, Cho, HJ, Jang, W, et al. A case of pathologically confirmed corticobasal degeneration initially presenting as progressive supranuclear palsy syndrome. J Korean Med Sci 2022;37(22):e183.CrossRefGoogle ScholarPubMed
Neumann, M, Lee, EB, Mackenzie, IR. Frontotemporal lobar degeneration TDP-43-immunoreactive pathological subtypes: clinical and mechanistic significance. Adv Exp Med Biol 2021;1281:201–217.CrossRefGoogle ScholarPubMed
Mackenzie, IR, Neumann, M, Bigio, EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 2010;119:1–4.CrossRefGoogle ScholarPubMed
Mackenzie, IR, Shi, J, Shaw, CL, et al. Dementia lacking distinctive histology (DLDH) revisited. Acta Neuropathol 2006;112:551–559.CrossRefGoogle ScholarPubMed
Kovacs, GG, Rozemuller, AJ, van Swieten, JC, et al. Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: a study of the BrainNet Europe Consortium. Neuropathol Appl Neurobiol 2013;39:166–178.CrossRefGoogle ScholarPubMed
Komori, T. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Brain Pathol 1999;9:663–679.CrossRefGoogle ScholarPubMed
Dickson, DW. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. Basel: ISN Neuropath Press; 2003: 414.Google Scholar
Jesus-Hernandez, M, Mackenzie, IR, Boeve, BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72:245–256.CrossRefGoogle Scholar
Van der Zee, J, Gijselinck, I, Dillen, L, et al. A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats. Hum Mutat 2013;34:363–373.CrossRefGoogle ScholarPubMed
Lee, EB, Porta, S, Baer, GM, et al. Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol 2017;134:65–78.CrossRefGoogle ScholarPubMed
Neumann, M, Rademakers, R, Roeber, S, et al. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 2009;132:2922–2931.CrossRefGoogle ScholarPubMed
Adegbuyiro, A, Sedighi, F, Pilkington, AW 4th, Groover, S, Legleiter, J. Proteins containing expanded polyglutamine tracts and neurodegenerative disease. Biochemistry 2017;56:1199–1217.CrossRefGoogle ScholarPubMed
Choudhury, S, Chatterjee, S, Chatterjee, K. Clinical characterization of genetically diagnosed cases of spinocerebellar ataxia type 12 from India. Mov Disord Clin Pract 2018;5:39–46.CrossRefGoogle ScholarPubMed
Paulson, HL, Shakkottai, VG, Clark, HB, Orr, HT. Polyglutamine spinocerebellar ataxias – from genes to potential treatments. Nat Rev Neurosci 2017;18:613–626.CrossRefGoogle ScholarPubMed
Rüb, U, Seidel, K, Heinsen, H, et al. Huntington’s disease (HD): the neuropathology of a multisystem neurodegenerative disorder of the human brain. Brain Pathol 2016;26:726–740.CrossRefGoogle Scholar
Vonsattel, JP, Myers, RH, Stevens, TJ, et al. Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 1985;44:559–577.CrossRefGoogle ScholarPubMed
Brown, TG, Chen, L. Neuropathology of Huntington’s disease. In: Szejko, N, ed. From Pathophysiology to Treatment of Huntington’s Disease [Internet]. IntechOpen; 2022. Available from: http://dx.doi.org/10.5772/intechopen.94806.Google Scholar
Paulson, HL. The spinocerebellar ataxias. J Neuroophthalmol 2009;29:227–237.CrossRefGoogle ScholarPubMed
Seidel, K, Siswanto, S, Brunt, ER, et al. Brain pathology of spinocerebellar ataxias. Acta Neuropathol 2012;124:1–21.CrossRefGoogle ScholarPubMed
Harding, AE. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of the ‘the Drew family of Walworth’. Brain 1982;105(Pt 1):1–28.CrossRefGoogle ScholarPubMed
Sullivan, R, Yau, WY, O’Connor, E, Houlden, H. Spinocerebellar ataxia: an update. J Neurol 2019;266:533–544.CrossRefGoogle ScholarPubMed
Olmos, V, Gogia, N, Luttik, K, Haidery, F, Lim, J. The extra-cerebellar effects of spinocerebellar ataxia type 1 (SCA1): looking beyond the cerebellum. Cell Mol Life Sci 2022;79:404.CrossRefGoogle ScholarPubMed
Rub, U, Burk, K, Timmann, D, et al. Spinocerebellar ataxia type 1 (SCA1): new pathoanatomical and clinico-pathological insights. Neuropathol Appl Neurobiol 2012;38:665–680.CrossRefGoogle ScholarPubMed
Velazquez-Perez, LC, Rodriguez-Labrada, R, Fernandez-Ruiz, J. Spinocerebellar ataxia type 2: clinicogenetic aspects, mechanistic insights, and management approaches. Front Neurol 2017;8.CrossRefGoogle ScholarPubMed
Yamada, M, Sato, T, Tsuji, S, Takahashi, H. CAG repeat disorder models and human europathology: similarities and differences. Acta Neuropathol 2008;115:71–86.CrossRefGoogle Scholar
Paulson, H, Shakkottai, V. Spinocerebellar ataxia type 3. 1998 [updated 2020]. In: Adam, MP, Everman, DB, Mirzaa, GM, et al., eds. GeneReviews® [Internet]. Seattle: University of Washington, Seattle; 1993–2023. Available from: www.ncbi.nlm.nih.gov/books/NBK1196/Google Scholar
Rüb, U, Gierga, K, Brunt, ER, et al. Spinocerebellar ataxias types 2 and 3: degeneration of the pre-cerebellar nuclei isolates the three phylogenetically defined regions of the cerebellum. J Neural Transm (Vienna) 2005;112:1523–1545.CrossRefGoogle ScholarPubMed
Rüb, U, Brunt, ER, Petrasch-Parwez, E, et al. Degeneration of ingestion-related brainstem nuclei in spinocerebellar ataxia type 2, 3, 6 and 7. Neuropathol Appl Neurobiol 2006;32:635–649.CrossRefGoogle ScholarPubMed
La Spada, AR. Spinocerebellar ataxia type 7. 1998 [updated 2020 Jul 23]. In: Adam, MP, Everman, DB, Mirzaa, GM, et al., eds. GeneReviews® [Internet]. Seattle: University of Washington, Seattle; 1993–2023. Available from: www.ncbi.nlm.nih.gov/books/NBK1256/Google Scholar
Parchi, P, Strammiello, R, Giese, A, Kretzschmar, H. Phenotypic variability of sporadic human prion disease and its molecular basis: past, present, and future. Acta Neuropathol 2011;121:91–112.CrossRefGoogle ScholarPubMed
Han, S, Seladi-Schulman, J. What is prion disease. www.healthline.com/health/prion-disease#types. 2022.Google Scholar
Ho, M, Sharma, R, Knipe, H, et al. Creutzfeldt–Jakob disease. Radiopaedia.org. 2023. https://radiopaedia.org/articles/7269Google Scholar
Iwasaki, Y. Creutzfeldt–Jakob disease. Neuropathology 2017;37:174–188.CrossRefGoogle ScholarPubMed
Baiardi, S, Romana Rizzi, R, Capellari, S, et al. Gerstmann–Sträussler–Scheinker disease (PRNP p.D202N) presenting with atypical parkinsonism. Neurol Genet 2020;6:e400.CrossRefGoogle ScholarPubMed
Jansen, C, Parchi, P, Capellari, S, et al. Human prion diseases in The Netherlands (1998–2009): clinical, genetic and molecular aspects. PLoS One 2012;7:e36333.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×