Abstract
Neurodegenerative disorders are complex, and heterogeneity is the rule, rather than the exception, even within a single disease entity. Neurodegenerative diseases can present clinically with predominantly cognitive symptoms (i.e., Alzheimer disease, fronto-temporal dementia, Lewy body dementia) or predominantly motor symptoms (i.e., Parkinson’s disease, Huntington disease, spinocerebellar ataxia).
Histologic changes include formation of abnormal structures in an extracellular location (amyloid deposits), in intracellular locations (intraneuronal: neurofibrillary tangle (NFT)), intracytoplasmic (Pick body, Lewy body), oligodendroglial (Papp-Lantos body), and other inclusions. Furthermore, loss of neurons, loss of synapses, glial changes, and vascular changes occur.
The molecular classification of neurodegenerative diseases differentiates between disorders with amyloid pathology, tauopathies, α-synucleinopathies, trinucleotide repeat disorders. Other genes involved include FUS, TDP-43, C9orf72, microtubule-associated proteins tau (MAPT), ubiquilin, ubiquilin 2, optineurin, and progranulin. Molecular pathways involve deposition of ß-sheet-rich proteins, protein-processing systems, unfolded protein response, ubiquitin-proteasome system, autophagy-lysosome pathway, modifications of disease-related proteins, maturation of protein deposits, neuronal loss due to different pathogenic pathways, metabolic changes, ion homeostasis, and neuro-inflammatory mechanisms.
The amyloid cascade hypothesis is discussed. Biomarker-based diagnostic algorithms for dementia syndromes are presented. A brief sketch of the differential diagnoses is presented including Pick disease, primary progressive aphasia (PPA), motor neuron disease with dementia, dementia lacking distinctive histopathology (DLDH), progressive subcortical gliosis (PSG), Parkinson’s disease with dementia, chromosome 17-associated dementia (Desinhibition-Dementia-Parkinsonism-Amyotrophy Complex), familial presenile dementia with tangles (FPDT), meso-limbo-cortical dementia Down syndrome (Trisomy 21), diffuse neurofibrillary tangles with calcifications (DNTC), thalamic degeneration, (non)-hereditary bilateral striatal necrosis, neuroacanthocytosis, pallidal degenerations, dentato-rubro-pallido-luysii degeneration, substantia reticularis degeneration, argyrophilic grain disease (AGD), adult polyglucosan body disease (APBD), normal pressure hydrocephalus (NPH), mitochondrial encephalomyopathies (Kearns-Sayre syndrome (KKS), myoclonic epilepsy with ragged-red fibers (MERF), mitochondrial encephalopathy, lactate, acidosis, and stroke-like episodes (MELAS), mitochondrial neurogastrointestinal encephalopathy (MNGIE)), Hallervorden-Spatz Disease, leukodystrophies, Wilson disease or hepato-lenticular degeneration, and dementia pugilistica.
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Selected References
Alonso ME, Teixeira F, Jimenez G, Escobar A (1989) Chorea-acanthocytosis: report of a family and neuropathological study of two cases. Can J Neurol Sci 16(4):426–431
Arai N (1989) “Grumose degeneration” of the dentate nucleus. A light and electron microscopic study in progressive supranuclear palsy and dentatorubropallidoluysial atrophy. J Neurol Sci 90(2):131–145
Arai N, Yagishita S, Amano N, Iwabuchi K, Misugi K (1989) “Grumose degeneration” of Tretiakoff. J Neurol Sci 94(1-3):319–323
Atkin G, Paulson H (2014) Ubiquitin pathways in neurodegenerative disease. Front Mol Neurosci 7:63. https://doi.org/10.3389/fnmol.2014.00063
Bertini E, D’Amico A (2009) Mitochondrial encephalomyopathies and related syndromes: brief review. Endocr Dev 14:38–52
Bird TD, Cederbaum S, Valey RW, Stahl WL (1978) Familial degeneration of the basal ganglia with acanthocytosis: a clinical, neuropathological, and neurochemical study. Ann Neurol 3(3):253–258. https://doi.org/10.1002/ana.410030312
Boespflug-Tanguy O, Labauge P, Fogli A, Vaurs-Barriere C (2008) Genes involved in leukodystrophies: a glance at glial functions. Curr Neurol Neurosci Rep 8(3):217–229
Bokhari MR, Bokhari SRA (2018) Hallervorden Spatz disease (Pantothenate kinase-associated neurodegeneration, PKAN). In: StatPearls. StatPearls Publishing LLC, Treasure Island, FL
Boxer AL (2011) Frontotemporal dementia. In: Budson AE, Kowall NW (eds) The handbook of Alzheimer’s disease and Other dementias. Wiley-Blackwell, Hoboken, NJ, pp 145–178
Braak H, Braak E (1987) Argyrophilic grains: characteristic pathology of cerebral cortex in cases of adult onset dementia without Alzheimer changes. Neurosci Lett 76(1):124–127
Braak H, Braak E (1988) Neuropil threads occur in dendrites of tangle-bearing nerve cells. Neuropathol Appl Neurobiol 14(1):39–44
Braak H, Braak E (1989) Cortical and subcortical argyrophilic grains characterize a disease associated with adult onset dementia. Neuropathol Appl Neurobiol 15(1):13–26
Braak H, Braak E (1998) Argyrophilic grain disease: frequency of occurrence in different age categories and neuropathological diagnostic criteria. J Neural Transm 105(8-9):801–819. https://doi.org/10.1007/s007020050096
Bridi JC, Hirth F (2018) Mechanisms of alpha-Synuclein induced synaptopathy in Parkinson’s disease. Front Neurosci 12:80. https://doi.org/10.3389/fnins.2018.00080
Bruyn GW (1986) Choreo-acanthocytosis. In: Vinken PJ, Bruyn GW, Klawans HL (eds) Handbook of clinical neurology, Extrapyramidal disorders, vol 5. Elsevier, Amsterdam, pp 327–334
Burre J (2015) The synaptic function of alpha-synuclein. J Park Dis 5(4):699–713. https://doi.org/10.3233/jpd-150642
Burre J, Sharma M, Sudhof TC (2018) Cell biology and pathophysiology of alpha-synuclein. Cold Spring Harb Perspect Med 8(3). https://doi.org/10.1101/cshperspect.a024091
Byrne SC, Rowland LP, Vonsattel JPG, Welzel AT, Walsh DM, Hardiman O (2011) Common themes in the pathogenesis of neurodegeneration. In: Hardiman O, Doherty CP (eds) Neurodegenerative disorders. Springer, Berlin, pp 1–15
Chang IJ, Hahn SH (2017) The genetics of Wilson disease. Handb Clin Neurol 142:19–34. https://doi.org/10.1016/b978-0-444-63625-6.00002-1
Chaturvedi S, Bala K, Thakur R, Suri V (2005) Mitochondrial encephalomyopathies: advances in understanding. Med Sci Monit 11(7):Ra238–Ra246
Costello DJ, Eichler AF, Eichler FS (2009) Leukodystrophies: classification, diagnosis, and treatment. Neurologist 15(6):319–328. https://doi.org/10.1097/NRL.0b013e3181b287c8
Critchley EM, Clark DB, Wikler A (1968) Acanthocytosis and neurological disorder without betalipoproteinemia. Arch Neurol 18(2):134–140
Czlonkowska A, Litwin T, Chabik G (2017) Wilson disease: neurologic features. Handb Clin Neurol 142:101–119. https://doi.org/10.1016/b978-0-444-63625-6.00011-2
Di Giorgio ML, Esposito A, Maccallini P, Micheli E, Bavasso F, Gallotta I, Verni F, Feiguin F, Cacchione S, McCabe BD, Di Schiavi E, Raffa GD (2017) WDR79/TCAB1 plays a conserved role in the control of locomotion and ameliorates phenotypic defects in SMA models. Neurobiol Dis 105:42–50. https://doi.org/10.1016/j.nbd.2017.05.005
DiMauro S (1996) Mitochondrial encephalomyopathies: what next? J Inherit Metab Dis 19(4):489–503
Ederle H, Dormann D (2017) TDP-43 and FUS en route from the nucleus to the cytoplasm. FEBS Lett 591(11):1489–1507. https://doi.org/10.1002/1873-3468.12646
Ferrer I, Santpere G, van Leeuwen FW (2008) Argyrophilic grain disease. Brain 131(Pt 6):1416–1432. https://doi.org/10.1093/brain/awm305
Fong TG, Press DZ (2011) Dementia with Lewy bodies. In: Budson AE, Kowall NW (eds) The handbook of Alzheimer’s disease and other dementias. Wiley-Blackwell, Hoboken, NJ, pp 131–144
Galloway PG, Mulvihill P, Siedlak S, Mijares M, Kawai M, Padget H, Kim R, Perry G (1990) Immunochemical demonstration of tropomyosin in the neurofibrillary pathology of Alzheimer’s disease. Am J Pathol 137(2):291–300
Geetha T, Vishwaprakash N, Sycheva M, Babu JR (2012) Sequestosome 1/p62: across diseases. Biomarkers 17(2):99–103. https://doi.org/10.3109/1354750x.2011.653986
Geser F, Martinez-Lage M, Kwong LK, Lee VM, Trojanowski JQ (2009) Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J Neurol 256(8):1205–1214. https://doi.org/10.1007/s00415-009-5069-7
Geser F, Lee VM, Trojanowski JQ (2010) Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies. Neuropathology 30(2):103–112. https://doi.org/10.1111/j.1440-1789.2009.01091.x
Geser F, Prvulovic D, O'Dwyer L, Hardiman O, Bede P, Bokde AL, Trojanowski JQ, Hampel H (2011) On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia. Prog Neurobiol 95(4):649–662. https://doi.org/10.1016/j.pneurobio.2011.08.011
Giannakopoulos P, Hof PR, Bouras C (1995) Dementia lacking distinctive histopathology: clinicopathological evaluation of 32 cases. Acta Neuropathol 89(4):346–355
Gordon HB, Letsou A, Bonkowsky JL (2014) The leukodystrophies. Acta Neuropathol 34(3):312–320. https://doi.org/10.1007/s00401-017-1739-1
Gregory A, Hayflick SJ (1993) Pantothenate kinase-associated neurodegeneration. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews ((R)). University of Washington, Seattle
Grundke-Iqbal I, Iqbal K, Tug YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83(13):4913–4917
Guerrero EN, Wang H, Mitra J, Hegde PM, Stowell SE, Liachko NF, Kraemer BC, Garruto RM, Rao KS, Hegde ML (2016) TDP-43/FUS in motor neuron disease: complexity and challenges. Prog Neurobiol 145-146:78–97. https://doi.org/10.1016/j.pneurobio.2016.09.004
Hardie RJ (1989) Acanthocytosis and neurological impairment—a review. Q J Med 71(264):291–306
Hardie RJ, Pullon HW, Harding AE, Owen JS, Pires M, Daniels GL, Imai Y, Misra VP, King RH, Jacobs JM et al (1991) Neuroacanthocytosis. A clinical, haematological and pathological study of 19 cases. Brain 114(Pt 1A):13–49
Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185
Hartig MB, Prokisch H, Meitinger T, Klopstock T (2012) Pantothenate kinase-associated neurodegeneration. Curr Drug Targets 13(9):1182–1189
Hayden EY, Teplow DB (2013) Amyloid beta-protein oligomers and Alzheimer’s disease. Alzheimer’s Res Ther 5(6):60. https://doi.org/10.1186/alzrt226
Herrup K (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18(6):794–799. https://doi.org/10.1038/nn.4017
Hirano A, Dembitzer HM, Kurland LT, Zimmerman HM (1968a) The fine structure of some intraganglionic alterations. Neurofibrillary tangles, granulovacuolar bodies and “rod-like” structures as seen in Guam amyotrophic lateral sclerosis and parkinsonism-dementia complex. J Neuropathol Exp Neurol 27(2):167–182
Hirano A, Tuazon R, Zimmerman HM (1968b) Neurofibrillary changes, granulovacuolar bodies and argentophilic globules observed in tuberous sclerosis. Acta Neuropathol 11(3):257–261
Iizuka R, Hirayama K (1986) Dentato-rubro-pallido-luysian atroph. In: Vinken PJ, Bruyn GW, Klawans HL (eds) Handbook of clinical neurology, vol 5. Elsevier, Amsterdam, pp 437–443
Iizuka R, Hirayama K, Maehara KA (1984) Dentato-rubro-pallido-luysian atrophy: a clinico-pathological study. J Neurol Neurosurg Psychiatry 47(12):1288–1298
Ikeda K, Akiyama H, Arai T, Matsushita M, Tsuchiya K, Miyazaki H (2000) Clinical aspects of argyrophilic grain disease. Clin Neuropathol 19(6):278–284
Ishigaki S, Sobue G (2018) Importance of functional loss of FUS in FTLD/ALS. Front Mol Biosci 5:44. https://doi.org/10.3389/fmolb.2018.00044
Iwaki T, Kume-Iwaki A, Goldman JE (1990) Cellular distribution of alpha B-crystallin in non-lenticular tissues. J Histochem Cytochem 38(1):31–9
Jansen AH, Reits EA, Hol EM (2014) The ubiquitin proteasome system in glia and its role in neurodegenerative diseases. Front Mol Neurosci 7:73. https://doi.org/10.3389/fnmol.2014.00073
Kelly C, Pericleous M (2018) Wilson disease: more than meets the eye. Postgrad Med J 94(1112):335–347. https://doi.org/10.1136/postgradmedj-2017-135381
Knowles TP, Vendruscolo M, Dobson CM (2014) The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol 15(6):384–396. https://doi.org/10.1038/nrm3810
Kohler W (2010) Leukodystrophies with late disease onset: an update. Curr Opin Neurol 23(3):234–241. https://doi.org/10.1097/WCO.0b013e328338313a
Kohler W, Curiel J, Vanderver A (2018) Adulthood leukodystrophies. Nat Rev Neurol 14(2):94–105. https://doi.org/10.1038/nrneurol.2017.175
Komatsu M, Kageyama S, Ichimura Y (2012) p62/SQSTM1/A170: physiology and pathology. Pharmacol Res 66(6):457–462. https://doi.org/10.1016/j.phrs.2012.07.004
Kosaka K (1994) Diffuse neurofibrillary tangles with calcification: a new presenile dementia. J Neurol Neurosurg Psychiatry 57(5):594–596
Kovacs GG (2014) Neuropathology of neurodegenerative diseases book and online: a practical guide. Cambridge University Press, Cambridge
Kummer MP, Heneka MT (2014) Truncated and modified amyloid-beta species. Alzheimer’s Res Ther 6(3):28. https://doi.org/10.1186/alzrt258
Lantos PL (1992) Neuropathology of unusual dementias: an overview. Baillieres Clin Neurol 1(3):485–516
Levine IM, Estes JW, Looney JM (1968) Hereditary neurological disease with acanthocytosis. A new syndrome. Arch Neurol 19(4):403–409
Ling SC (2018) Synaptic paths to neurodegeneration: the emerging role of TDP-43 and FUS in synaptic functions. Neural Plast 2018:8413496. https://doi.org/10.1155/2018/8413496
Lo C, Bandmann O (2017) Epidemiology and introduction to the clinical presentation of Wilson disease. Handb Clin Neurol 142:7–17. https://doi.org/10.1016/b978-0-444-63625-6.00008-2
Love S, Saitoh T, Quijada S, Cole GM, Terry RD (1988) Alz-50, ubiquitin and tau immunoreactivity of neurofibrillary tangles, Pick bodies and Lewy bodies. J Neuropathol Exp Neurol 47(4):393–405
Lowe J, Mayer RJ (1990) Ubiquitin, cell stress and diseases of the nervous system. Neuropathol Appl Neurobiol 16(4):281–91
Mayer RJ, Lowe J, Landon M (1991) Ubiquitin and the molecular pathology of chronic degenerative diseases. J Pathol 163(4):279–81
Mikhaleva S, Lemke EA (2018) Beyond the transport function of import receptors: what’s all the FUS about? Cell 173(3):549–553. https://doi.org/10.1016/j.cell.2018.04.002
Mukoyama M, Kazui H, Sunohara N, Yoshida M, Nonaka I, Satoyoshi E (1986) Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes with acanthocytosis: a clinicopathological study of a unique case. J Neurol 233(4):228–32
Nolan M, Talbot K, Ansorge O (2016) Pathogenesis of FUS-associated ALS and FTD: insights from rodent models. Acta Neuropathol Commun 4(1):99. https://doi.org/10.1186/s40478-016-0358-8
Ohama E, Ohara S, Ikuta F, Tanaka K, Nishizawa M, Miyatake T (1987) Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathol 74(3):226–33
Oldfors A, Tulinius M (2003) Mitochondrial encephalomyopathies. J Neuropathol Exp Neurol 62(3):217–227
Perlman SJ, Mar S (2012) Leukodystrophies. Adv Exp Med Biol 724:154–171. https://doi.org/10.1007/978-1-4614-0653-2_13
Poujois A, Mikol J, Woimant F (2017) Wilson disease: brain pathology. Handb Clin Neurol 142:77–89. https://doi.org/10.1016/b978-0-444-63625-6.00008-2
Ratti A, Buratti E (2016) Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins. J Neurochem 138(Suppl 1):95–111. https://doi.org/10.1111/jnc.13625
Sakai T, Mawatari S, Iwashita H, Goto I, Kuroiwa Y (1981) Choreoacanthocytosis. Clues to clinical diagnosis. Arch Neurol 38(6):335–338
Salminen A, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H, Alafuzoff I (2012) Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer’s disease. Prog Neurobiol 96(1):87–95. https://doi.org/10.1016/j.pneurobio.2011.11.005
Sarnat HB, Marin-Garcia J (2005) Pathology of mitochondrial encephalomyopathies. Can J Neurol Sci 32(2):152–166
Schilsky ML (2017) Wilson disease: diagnosis, treatment, and follow-up. Postgrad Med J 21(4):755–767. https://doi.org/10.1136/postgradmedj-2017-135381
Simchowicz T (1911) Histologische Studien über die senile Demenz. Histol Histopathol Arb Grosshirnrinde 4:267–444
Smith JK (1975) Dentatorubropallidoluysian atrophy. In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology, vol 21. Elsevier-North Holland, Amsterdam, pp 519–534
Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12(6):609–622. https://doi.org/10.1016/s1474-4422(13)70090-5
Takashima A (2013) Tauopathies and tau oligomers. J Alzheimers Dis 37(3):565–568. https://doi.org/10.3233/jad-130653
Theillet FX, Binolfi A, Bekei B, Martorana A, Rose HM, Stuiver M, Verzini S, Lorenz D, van Rossum M, Goldfarb D, Selenko P (2016) Structural disorder of monomeric alpha-synuclein persists in mammalian cells. Nature 530(7588):45–50. https://doi.org/10.1038/nature16531
Thomas M, Alegre-Abarrategui J, Wade-Martins R (2013) RNA dysfunction and aggrephagy at the centre of an amyotrophic lateral sclerosis/frontotemporal dementia disease continuum. Brain 136(Pt 5):1345–1360. https://doi.org/10.1093/brain/awt030
Tolnay M, Clavaguera F (2004) Argyrophilic grain disease: a late-onset dementia with distinctive features among tauopathies. Neuropathology 24(4):269–283
Tolnay M, Probst A (2008) Argyrophilic grain disease. Handb Clin Neurol 89:553–563. https://doi.org/10.1016/s0072-9752(07)01251-1
Tolnay M, Schwietert M, Monsch AU, Staehelin HB, Langui D, Probst A (1997a) Argyrophilic grain disease: distribution of grains in patients with and without dementia. Acta Neuropathol 94(4):353–358
Tolnay M, Spillantini MG, Goedert M, Ulrich J, Langui D, Probst A (1997b) Argyrophilic grain disease: widespread hyperphosphorylation of tau protein in limbic neurons. Acta Neuropathol 93(5):477–484
Tolnay M, Mistl C, Ipsen S, Probst A (1998) Argyrophilic grains of Braak: occurrence in dendrites of neurons containing hyperphosphorylated tau protein. Neuropathol Appl Neurobiol 24(1):53–59
Tolnay M, Monsch AU, Probst A (2001) Argyrophilic grain disease. A frequent dementing disorder in aged patients. Adv Exp Med Biol 487:39–58
Tolnay M, Sergeant N, Ghestem A, Chalbot S, De Vos RA, Jansen Steur EN, Probst A, Delacourte A (2002) Argyrophilic grain disease and Alzheimer’s disease are distinguished by their different distribution of tau protein isoforms. Acta Neuropathol 104(4):425–434. https://doi.org/10.1007/s00401-002-0591-z
University of Washington, Seattle (1993–2019). GeneReviews is a registered trademark of the University of Washington, Seattle, WA. All rights reserved
Valdinocci D, Radford RA, Siow SM, Chung RS, Pountney DL (2017) Potential modes of intercellular alpha-synuclein transmission. Int J Mol Sci 18(2):E469. https://doi.org/10.3390/ijms18020469
Van Craenenbroeck A, Gebruers M, Martin JJ, Cras P (2010) Hallervorden-Spatz disease: historical case presentation in the spotlight of nosological evolution. Mov Disord 25(15):2486–2492. https://doi.org/10.1002/mds.23217
van der Knaap MS, Bugiani M (2017) Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol 134(3):351–382. https://doi.org/10.1007/s00401-017-1739-1
Varela JM (1969) Atrophy of the reticular formation of the central nervous system. I. Generalized global reticular atrophy. Syndrome of dyshomeostasis of the central nervous system. Psychiatr Clin 2(1):41–61
Zimbrean P, Seniow J (2017) Cognitive and psychiatric symptoms in Wilson disease. Handb Clin Neurol 142:121–140. https://doi.org/10.1016/b978-0-444-63625-6.00003-3
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Weis, S. et al. (2019). Neurodegeneration: General Aspects. In: Imaging Brain Diseases. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1544-2_30
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