Abstract
In Parkinson disease (PD), pathological processes and neurodegeneration begin long before the cardinal motor symptoms develop and enable clinical diagnosis. In this prodromal phase, risk and prodromal markers can be used to identify individuals who are likely to develop PD, as in the recently updated International Parkinson and Movement Disorders Society research criteria for prodromal PD. However, increasing evidence suggests that clinical and prodromal PD are heterogeneous, and can be classified into subtypes with different clinical manifestations, pathomechanisms and patterns of spatial and temporal progression in the CNS and PNS. Genetic, pathological and imaging markers, as well as motor and non-motor symptoms, might define prodromal subtypes of PD. Moreover, concomitant pathology or other factors, including amyloid-β and tau pathology, age and environmental factors, can cause variability in prodromal PD. Patients with REM sleep behaviour disorder (RBD) exhibit distinct patterns of α-synuclein pathology propagation and might indicate a body-first subtype rather than a brain-first subtype. Identification of prodromal PD subtypes and a full understanding of variability at this stage of the disease is crucial for early and accurate diagnosis and for targeting of neuroprotective interventions to ensure efficacy.
Key points
-
Heterogeneity of Parkinson disease (PD) starts in the prodromal phase.
-
Pathological spread, imaging markers and the onset and progression of motor and non-motor symptoms are variable in prodromal PD.
-
The variability in clinical phenotype suggests that subtypes of prodromal PD can be defined.
-
Possible subtypes of prodromal PD are REM sleep behaviour disorder subtypes, brain-first and body-first subtypes, genetic subtypes and biological subtypes.
-
Variability in prodromal PD must result from different pathophysiological mechanisms; defining prodromal subtypes is the first step to identifying the biological difference.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
£14.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
£139.00 per year
only £11.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Mahlknecht, P., Seppi, K. & Poewe, W. The concept of prodromal Parkinson’s disease. J. Parkinson’s Dis. 5, 681–697 (2015).
Ahmadi, S. A. et al. Analyzing the co-localization of substantia nigra hyper-echogenicities and iron accumulation in Parkinson’s disease: a multi-modal atlas study with transcranial ultrasound and MRI. NeuroImage Clin. 26, 102185 (2020).
Berg, D. et al. Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease. Mov. Disord. 29, 454–462 (2014).
Savica, R. et al. Medical records documentation of constipation preceding Parkinson disease: a case-control study. Neurology 73, 1752–1758 (2009).
Schrag, A., Horsfall, L., Walters, K., Noyce, A. & Petersen, I. Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study. Lancet Neurol. 14, 57–64 (2015). Very large case–control study that showed higher incidence rates of several autonomic, neuropsychiatric and motor features in individuals 2, 5 and 10 years before diagnosis of PD compared with PD-free individuals using primary care data.
Gustafsson, H., Nordstrom, A. & Nordstrom, P. Depression and subsequent risk of Parkinson disease: a nationwide cohort study. Neurology 84, 2422–2429 (2015).
Fereshtehnejad, S. M. et al. Evolution of prodromal Parkinson’s disease and dementia with Lewy bodies: a prospective study. Brain 142, 20151–22067 (2019). In this study, natural evolution of various motor and non-motor manifestations of parkinsonism is analysed using real-life longitudinal clinical data from an RBD cohort.
Postuma, R. B. et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov. Disord. 30, 1591–1601 (2015).
Greenland, J. C., Williams-Gray, C. H. & Barker, R. A. The clinical heterogeneity of Parkinson’s disease and its therapeutic implications. Eur. J. Neurosci. 49, 328–338 (2019).
Iwaki, H. et al. Genetic risk of Parkinson disease and progression: an analysis of 13 longitudinal cohorts. Neurol. Genet. 5, e348 (2019).
Fereshtehnejad, S.-M. et al. New clinical subtypes of Parkinson disease and their longitudinal progression. JAMA Neurol. 72, 863–873 (2015).
De Pablo-Fernández, E., Lees, A. J., Holton, J. L. & Warner, T. T. Prognosis and neuropathologic correlation of clinical subtypes of Parkinson disease. JAMA Neurol. 76, 470–479 (2019).
Bäckström, D. et al. Early predictors of mortality in parkinsonism and Parkinson disease: a population-based study. Neurology 91, e2045–e2056 (2018).
Hou, Y. et al. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15, 565–581 (2019).
Knudsen, K. et al. In-vivo staging of pathology in REM sleep behaviour disorder: a multimodality imaging case-control study. Lancet. Neurol. 17, 618–628 (2018). Multimodal neuroimaging study showing a caudorostral gradient of dysfunction in RBD patients suggesting that pathological spread in PD may initially involve peripheral autonomic nerves and subsequently the rostral brainstem.
Doppler, K. et al. Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson’s disease. Acta Neuropathol. 133, 535–545 (2017).
Johnson, M. E., Stecher, B., Labrie, V., Brundin, L. & Brundin, P. Triggers, facilitators, and aggravators: redefining Parkinson’s disease pathogenesis. Trends Neurosci. 42, 4–13 (2019).
Titova, N., Padmakumar, C., Lewis, S. J. G. & Chaudhuri, K. R. Parkinson’s: a syndrome rather than a disease? J. Neural Transm. 124, 907–914 (2017).
Adler, C. H. et al. Unified staging system for Lewy body disorders: clinicopathologic correlations and comparison to Braak staging. J. Neuropathol. Exp. Neurol. 78, 891–899 (2019).
Kaufmann, H. et al. Natural history of pure autonomic failure: a United States prospective cohort. Ann. Neurol. 81, 287–297 (2017).
Walker, L., Stefanis, L. & Attems, J. Clinical and neuropathological differences between Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies – current issues and future directions. J. Neurochem. 150, 467–474 (2019).
Postuma, R. B. et al. Abolishing the 1-year rule: How much evidence will be enough? Mov. Disord. 31, 1623–1627 (2016).
Surmeier, D. J., Obeso, J. A. & Halliday, G. M. Selective neuronal vulnerability in Parkinson disease. Nat. Rev. Neurosci. 18, 101–113 (2017).
Giguère, N., Nanni, S. B. & Trudeau, L. E. On cell loss and selective vulnerability of neuronal populations in Parkinson’s disease. Front. Neurol. 9, 455 (2018).
Berg, D. et al. MDS research criteria for prodromal Parkinson’s disease. Mov. Disord. 30, 1600–1611 (2015). Original MDS research criteria for prodromal PD proposing an evidence-based method considering risk/prodromal marker evidence from prospective studies and a Bayesian classifier approach that allows the calculation of prodromal PD probabilities based on age and individual marker profiles.
Heinzel, S. et al. Update of the MDS research criteria for prodromal Parkinson’s disease. Mov. Disord. 34, 1464–1470 (2019). Most recent version of the MDS research criteria for prodromal PD with updated predictive values of markers, introduction of four new markers, new approaches to consider genetic risk markers for PD prediction, and a web-based calculator.
Schrag, A., Anastasiou, Z., Ambler, G., Noyce, A. & Walters, K. Predicting diagnosis of Parkinson’s disease: a risk algorithm based on primary care presentations. Mov. Disord. 34, 480–486 (2019).
Anheim, M. et al. Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers. Neurology 78, 417–420 (2012).
Lee, A. J. et al. Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry. Mov. Disord. 32, 1432–1438 (2017).
Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18, 1091–1102 (2019).
Nerius, M., Doblhammer, G. & Tamgüney, G. GI infections are associated with an increased risk of Parkinson’s disease. Gut 69, 1154–1156 (2020).
Marras, C., Canning, C. G. & Goldman, S. M. Environment, lifestyle, and Parkinson’s disease: implications for prevention in the next decade. Mov. Disord. 34, 801–811 (2019).
Darweesh, S. K. L. et al. Trajectories of prediagnostic functioning in Parkinson’s disease. Brain 140, 429–441 (2017).
Jennings, D. et al. Conversion to Parkinson disease in the PARS hyposmic and dopamine transporter-deficit prodromal cohort. JAMA Neurol. 74, 933–940 (2017).
Fereshtehnejad, S.-M. et al. Validation of the MDS research criteria for prodromal Parkinson’s disease: longitudinal assessment in a REM sleep behavior disorder (RBD) cohort. Mov. Disord. 32, 865–873 (2017).
Mahlknecht, P. et al. Performance of the Movement Disorders Society criteria for prodromal Parkinson’s disease: a population-based 10-year study. Mov. Disord. 33, 405–413 (2018).
Mirelman, A. et al. Application of the Movement Disorder Society prodromal criteria in healthy G2019S–LRRK2 carriers. Mov. Disord. 33, 966–973 (2018).
Pilotto, A. et al. Application of the Movement Disorder Society prodromal Parkinson’s disease research criteria in 2 independent prospective cohorts. Mov. Disord. 32, 1025–1034 (2017).
Tsukita, K., Sakamaki-Tsukita, H., Tanaka, K., Suenaga, T. & Takahashi, R. Value of in vivo α-synuclein deposits in Parkinson’s disease: a systematic review and meta-analysis. Mov. Disord. 34, 1452–1463 (2019).
Leclair-Visonneau, L. et al. REM sleep behavior disorder is related to enteric neuropathology in Parkinson disease. Neurology 89, 1612–1618 (2017).
Barber, T. R., Klein, J. C., Mackay, C. E. & Hu, M. T. M. Neuroimaging in pre-motor Parkinson’s disease. Neuroimage. Clin. 15, 215–227 (2017).
Del Din, S. et al. Gait analysis with wearables predicts conversion to Parkinson disease. Ann. Neurol. 86, 357–367 (2019).
Hobert, M. A. et al. Progressive gait deficits in Parkinson’s disease: a wearable-based biannual 5-year prospective study. Front. Aging Neurosci. 11, 22 (2019).
Merola, A. et al. Technology-based assessment of motor and nonmotor phenomena in Parkinson disease. Expert. Rev. Neurother. 18, 825–845 (2018).
Alonso, A., Huang, X., Mosley, T. H., Heiss, G. & Chen, H. Heart rate variability and the risk of Parkinson disease: the Atherosclerosis Risk in Communities Study. Ann. Neurol. 77, 877–883 (2015).
Heinzel, S. et al. Age- and sex-related heterogeneity in prodromal Parkinson’s disease. Mov. Disord. 33, 1025–1027 (2018).
Postuma, R. B. et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain 142, 744–759 (2019).
Alotaibi, F., Pelletier, A., Gagnon, J., Montplaisir, J. Y. & Postuma, R. B. Prodromal marker progression in idiopathic rapid eye movement sleep behavior disorder: sample size for clinical trials. Mov. Disord. 34, 1914–1919 (2019).
Schaeffer, E. et al. Patients’ views on the ethical challenges of early Parkinson disease detection. Neurology 94, e2037–e2044 (2020).
Anang, J. B. M. et al. Predictors of dementia in Parkinson disease: a prospective cohort study. Neurology 83, 1253–1260 (2014).
Dugger, B. N. et al. Concomitant pathologies among a spectrum of parkinsonian disorders. Park. Relat. Disord. 20, 525–529 (2014).
Robinson, J. L. et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 141, 2181–2193 (2018).
Fereshtehnejad, S. M. & Postuma, R. B. Subtypes of Parkinson’s disease: what do they tell us about disease progression? Curr. Neurol. Neurosci. Rep. 17, 34 (2017).
Kalia, L. V. et al. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol. 72, 100–105 (2015).
McKeith, I. G. et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology 94, 743–755 (2020).
de Lau, L. M. L., Verbaan, D., van Rooden, S. M., Marinus, J. & van Hilten, J. J. Relation of clinical subtypes in Parkinson’s disease with survival. Mov. Disord. 29, 150–151 (2014).
Simuni, T. et al. How stable are Parkinson’s disease subtypes in de novo patients: analysis of the PPMI cohort? Park. Relat. Disord. 28, 62–67 (2016).
Eisinger, R. S. et al. Motor subtype changes in early Parkinson’s disease. Park. Relat. Disord. 43, 67–72 (2017).
Alves, G., Larsen, J. P., Emre, M., Wentzel-Larsen, T. & Aarsland, D. Changes in motor subtype and risk for incident dementia in Parkinson’s disease. Mov. Disord. 21, 1123–1130 (2006).
Zhang, X. et al. Data-driven subtyping of Parkinson’s disease using longitudinal clinical records: a cohort study. Sci. Rep. 9, 797 (2019).
Fereshtehnejad, S. M., Zeighami, Y., Dagher, A. & Postuma, R. B. Clinical criteria for subtyping Parkinson’s disease: biomarkers and longitudinal progression. Brain 140, 1959–1976 (2017). Using a comprehensive data-driven approach, a new multi-domain subtyping method is suggested in this article that has been shown to connect with underlying pathological stages as well as imaging and CSF biomarkers. The authors provide a user-friendly guideline and calculator to assign every patient to a probable subtype.
Zeighami, Y. et al. Assessment of a prognostic MRI biomarker in early de novo Parkinson’s disease. Neuroimage Clin. 24, 101986 (2019).
Abbasi, N. et al. Predicting severity and prognosis in Parkinson’s disease from brain microstructure and connectivity. Neuroimage Clin. 25, 102111 (2020).
Postuma, R. B. et al. REM sleep behavior disorder and neuropathology in Parkinson’s disease. Mov. Disord. 30, 1413–1417 (2015).
Di Battista, M. E. et al. Intercepting Parkinson disease non-motor subtypes: a proof-of-principle study in a clinical setting. J. Neurol. Sci. 388, 186–191 (2018).
Marras, C. & Chaudhuri, K. R. Nonmotor features of Parkinson’s disease subtypes. Mov. Disord. 31, 1095–1102 (2016).
Sauerbier, A., Jenner, P., Todorova, A. & Chaudhuri, K. R. Non motor subtypes and Parkinson’s disease. Park. Relat. Disord. 22, S41–S46 (2016).
Kang, J. H. et al. CSF biomarkers associated with disease heterogeneity in early Parkinson’s disease: the Parkinson’s Progression Markers Initiative study. Acta Neuropathol. 131, 935–949 (2016).
Kang, J. H. et al. Association of cerebrospinal fluid β-amyloid 1-42, t-tau, p-tau 181, and α-synuclein levels with clinical features of drug-naive patients with early Parkinson disease. JAMA Neurol. 70, 1277–1287 (2013).
McMillan, C. T. & Wolk, D. A. Presence of cerebral amyloid modulates phenotype and pattern of neurodegeneration in early Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 87, 1112–1122 (2016).
Fairfoul, G. et al. Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann. Clin. Transl. Neurol. 3, 812–818 (2016).
Rossi, M. et al. Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol. 140, 49–62 (2020).
Antelmi, E., Donadio, V., Incensi, A., Plazzi, G. & Liguori, R. Skin nerve phosphorylated α-synuclein deposits in idiopathic REM sleep behavior disorder. Neurology 88, 2128–2131 (2017).
Vilas, D. et al. Assessment of α-synuclein in submandibular glands of patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. Lancet Neurol. 15, 708–718 (2016).
Iranzo, A. et al. α-Synuclein aggregates in labial salivary glands of idiopathic rapid eye movement sleep behavior disorder. Sleep 41, zsy101 (2018).
Sprenger, F. S. et al. Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder. Neurology 85, 1761–1768 (2015).
Lim, E. W. et al. Amyloid-β and Parkinson’s disease. J. Neurol. 266, 2605–2619 (2019).
Lawton, M. et al. Blood biomarkers with Parkinson’s disease clusters and prognosis: the Oxford Discovery Cohort. Mov. Disord. 35, 279–287 (2020).
Cheng, H.-C., Ulane, C. M. & Burke, R. E. Clinical progression in Parkinson disease and the neurobiology of axons. Ann. Neurol. 67, 715–725 (2010).
Bauckneht, M. et al. Presynaptic dopaminergic neuroimaging in REM sleep behavior disorder: a systematic review and meta-analysis. Sleep. Med. Rev. 41, 266–274 (2018).
Borghammer, P. & Van Den Berge, N. Brain-first versus gut-first Parkinson’s disease: a hypothesis. J. Parkinson’s Dis. 9, S281–S295 (2019).
Iranzo, A. et al. Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder. Ann. Neurol. 82, 419–428 (2017).
Iranzo, A. et al. Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study [corrected]. Lancet. Neurol. 9, 1070–1077 (2010).
Simuni, T. et al. Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson’s Progression Markers Initiative (PPMI): a cross-sectional study. Lancet Neurol. 19, 71–80 (2020).
Barber, T. R. et al. Nigrosome 1 imaging in REM sleep behavior disorder and its association with dopaminergic decline. Ann. Clin. Transl. Neurol. 7, 26–35 (2020).
Heller, J. et al. Brain imaging findings in idiopathic REM sleep behavior disorder (RBD) – a systematic review on potential biomarkers for neurodegeneration. Sleep. Med. Rev. 34, 23–33 (2017).
Unger, M. M. et al. Assessment of idiopathic rapid-eye-movement sleep behavior disorder by transcranial sonography, olfactory function test, and FP-CIT-SPECT. Mov. Disord. 23, 596–599 (2008).
Ehrminger, M. et al. The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder. Brain 139, 1180–1188 (2016).
Andersen, K. B. et al. Altered sensorimotor cortex noradrenergic function in idiopathic REM sleep behaviour disorder – a PET study. Park. Relat. Disord. 75, 63–69 (2020).
Bedard, M. A. et al. Brain cholinergic alterations in idiopathic REM sleep behaviour disorder: a PET imaging study with 18F-FEOBV. Sleep. Med. 58, 35–41 (2019).
Liu, S. Y. et al. The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson’s disease: a cross-sectional PET study. Lancet Neurol. 17, 309–316 (2018).
Wile, D. J. et al. Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies. Lancet Neurol. 16, 351–359 (2017).
Miyamoto, T. et al. Reduced cardiac 123I-MIBG scintigraphy in idiopathic REM sleep behavior disorder. Neurology 67, 2236–2238 (2006).
Kashihara, K., Imamura, T. & Shinya, T. Cardiac 123I-MIBG uptake is reduced more markedly in patients with REM sleep behavior disorder than in those with early stage Parkinson’s disease. Park. Relat. Disord. 16, 252–255 (2010).
Nagayama, H., Hamamoto, M., Ueda, M., Nagashima, J. & Katayama, Y. Reliability of MIBG myocardial scintigraphy in the diagnosis of Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 76, 249–251 (2005).
Horsager, J. et al. Brain-first vs. body-first Parkinson’s disease – a multi-modal imaging case-control study. Brain 143, 3077–3088 (2020). Case–control multimodal imaging study in PD patients with and without RBD showing that patients with RBD are characterized by initial colonic and cardiac signal loss (‘body-first’), whereas patients without RBD show primary putaminal signal loss (‘brain-first’).
Iranzo, A. et al. Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study. Lancet Neurol. 12, 443–453 (2013).
Iranzo, A. et al. Characterization of patients with longstanding idiopathic REM sleep behavior disorder. Neurology 89, 242–248 (2017).
Yao, C. et al. Longstanding disease-free survival in idiopathic REM sleep behavior disorder: is neurodegeneration inevitable? Park. Relat. Disord. 54, 99–102 (2018).
Dugger, B. N. et al. Rapid eye movement sleep behavior disorder and subtypes in autopsy-confirmed dementia with Lewy bodies. Mov. Disord. 27, 72–78 (2012).
Milber, J. M. et al. Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease. Neurology 79, 2307–2314 (2012).
Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).
Raunio, A. et al. Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85+. Acta Neuropathol. 138, 771–782 (2019).
McKeith, I. G. et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65, 1863–1872 (2005).
Kosaka, K., Yoshimura, M., Ikeda, K. & Budka, H. Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree – a new disease? Clin. Neuropathol. 3, 185–192 (1984).
Heinzel, S. et al. Gut microbiome signatures of risk and prodromal markers of Parkinson disease. Ann. Neurol. 88, 320–331 (2020).
Heintz-Buschart, A. et al. The nasal and gut microbiome in Parkinson’s disease and idiopathic rapid eye movement sleep behavior disorder. Mov. Disord. 33, 88–98 (2018).
Burbulla, L. F. et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science. 357, 1255–1261 (2017).
Paul, K. C., Schulz, J., Bronstein, J. M., Lill, C. M. & Ritz, B. R. Association of polygenic risk score with cognitive decline and motor progression in Parkinson disease. JAMA Neurol. 75, 360–366 (2018).
Zimmermann, M. et al. Patient’s perception: shorter and more severe prodromal phase in GBA-associated PD. Eur. J. Neurol. 26, 694–698 (2018).
Krohn, L. et al. GBA variants in REM sleep behavior disorder: a multicenter study. Neurology 95, e1008–e1016 (2020).
Pont-Sunyer, C. et al. The prodromal phase of leucine-rich repeat kinase 2-associated Parkinson disease: clinical and imaging studies. Mov. Disord. 32, 726–738 (2017).
Tolosa, E., Vila, M., Klein, C. & Rascol, O. LRRK2 in Parkinson disease: challenges of clinical trials. Nat. Rev. Neurol. 16, 97–107 (2020).
Antony, P. M. A., Diederich, N. J., Krüger, R. & Balling, R. The hallmarks of Parkinson’s disease. FEBS J. 280, 5981–5993 (2013).
Lin, K. J. et al. The overcrowded crossroads: mitochondria, alpha-synuclein, and the endo-lysosomal system interaction in Parkinson’s disease. Int. J. Mol. Sci. 20, 5312 (2019).
Braak, H. et al. Amygdala pathology in Parkinson’s disease. Acta Neuropathol. 88, 493–500 (1994).
Wakabayashi, K., Takahashi, H., Ohama, E. & Ikuta, F. Parkinson’s disease: an immunohistochemical study of Lewy body-containing neurons in the enteric nervous system. Acta Neuropathol. 79, 581–583 (1990).
Iwanaga, K. et al. Lewy body-type degeneration in cardiac plexus in Parkinson’s and incidental Lewy body diseases. Neurology 52, 1269–1271 (1999).
den Hartog Jager, W. A. & Bethlem, J. The distribution of Lewy bodies in the central and autonomic nervous systems in idiopathic paralysis agitans. J. Neurol. Neurosurg. Psychiatry 23, 283–290 (1960).
Halliday, G. M., Blumbergs, P. C., Cotton, R. G. H., Blessing, W. W. & Geffen, L. B. Loss of brainstem serotonin- and substance P-containing neurons in Parkinson’s disease. Brain Res. 510, 104–107 (1990).
Jellinger, K. Quantitative changes in some subcortical nuclei in aging, Alzheimer’s disease and Parkinson’s disease. Neurobiol. Aging 8, 556–561 (1987).
Wakabayashi, K. & Takahashi, H. Neuropathology of autonomic nervous system in Parkinson’s disease. Eur. Neurol. 38, 2–7 (1997).
Forno, L. S. Neuropathology of Parkinson’s disease. J. Neuropathol. Exp. Neurol. 55, 259–272 (1996).
Markesbery, W. R., Jicha, G. A., Liu, H. & Schmitt, F. A. Lewy body pathology in normal elderly subjects. J. Neuropathol. Exp. Neurol. 68, 816–822 (2009).
Braak, H., de Vos, R. A. I., Bohl, J. & Del Tredici, K. Gastric α-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci. Lett. 396, 67–72 (2006).
Desplats, P. et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009).
Hansen, C. et al. α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J. Clin. Invest. 121, 715–725 (2011).
Hawkes, C. H., Tredici, K. D. & Braak, H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol. Appl. Neurobiol. 33, 599–614 (2007).
Svensson, E. et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 78, 522–529 (2015).
Pan-Montojo, F. et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci. Rep. 2, 898 (2012).
Noorian, A. R. et al. Alpha-synuclein transgenic mice display age-related slowing of gastrointestinal motility associated with transgene expression in the vagal system. Neurobiol. Dis. 48, 9–19 (2012).
Lubomski, M. et al. Parkinson’s disease and the gastrointestinal microbiome. J. Neurol. 267, 2507–2523 (2019).
Burke, R. E., Dauer, W. T. & Vonsattel, J. P. G. A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann. Neurol. 64, 485–491 (2008).
Jellinger, K. A. A critical evaluation of current staging of α-synuclein pathology in Lewy body disorders. Biochim. Biophys. Acta Mol. Basis Dis. 1792, 730–740 (2009).
Jellinger, K. A. Is Braak staging valid for all types of Parkinson’s disease? J. Neural Transm. 126, 423–431 (2019).
Halliday, G., Hely, M., Reid, W. & Morris, J. The progression of pathology in longitudinally followed patients with Parkinson’s disease. Acta Neuropathol. 115, 409–415 (2008).
Ulusoy, A. et al. Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol. Med. 5, 1119–1127 (2013).
Arotcarena, M.-L. et al. Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates. Brain 143, 1462–1475 (2020).
Ulusoy, A. et al. Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections. Acta Neuropathol. 133, 381–393 (2017).
McKeith, I. G. et al. Diagnosis and management of dementia with Lewy bodies. Neurology 89, 88–100 (2017).
Kosaka, K. Latest concept of Lewy body disease. Psychiatry Clin. Neurosci. 68, 391–394 (2014).
Nakashima-Yasuda, H. et al. Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol. 114, 221–229 (2007).
Popescu, A., Lippa, C. F., Lee, V. M. Y. & Trojanowski, J. Q. Lewy bodies in the amygdala: increase of α-synuclein aggregates in neurodegenerative diseases with tau-based inclusions. Arch. Neurol. 61, 1915–1919 (2004).
Clinton, L. K., Blurton-Jones, M., Myczek, K., Trojanowski, J. Q. & LaFerla, F. M. Synergistic interactions between Aβ, tau, and α-synuclein: acceleration of neuropathology and cognitive decline. J. Neurosci. 30, 7281–7289 (2010).
Poulopoulos, M., Levy, O. A. & Alcalay, R. N. The neuropathology of genetic Parkinson’s disease. Mov. Disord. 27, 831–842 (2012).
Engelender, S. & Isacson, O. The threshold theory for Parkinson’s disease. Trends Neurosci. 40, 4–14 (2017).
Bassil, F. et al. Amyloid-Beta (Aβ) plaques promote seeding and spreading of alpha-synuclein and tau in a mouse model of Lewy body disorders with Aβ pathology. Neuron 105, 260–275 (2020).
Hall, S. et al. Longitudinal measurements of cerebrospinal fluid biomarkers in Parkinson’s disease. Mov. Disord. 31, 898–905 (2016).
Lehtonen, Š., Sonninen, T. M., Wojciechowski, S., Goldsteins, G. & Koistinaho, J. Dysfunction of cellular proteostasis in Parkinson’s disease. Front. Neurosci. 13, 457 (2019).
Elbaz, A. et al. CYP2D6 polymorphism, pesticide exposure, and Parkinson’s disease. Ann. Neurol. 55, 430–434 (2004).
Miyake, Y. et al. LRRK2 Gly2385Arg polymorphism, cigarette smoking, and risk of sporadic Parkinson’s disease: a case-control study in Japan. J. Neurol. Sci. 297, 15–18 (2010).
Goldman, S. M. et al. Head injury, alpha-synuclein Rep1, and Parkinson’s disease. Ann. Neurol. 71, 40–48 (2012).
Lee, P. C. et al. Examining the reserve hypothesis in Parkinson’s disease: a longitudinal study. Mov. Disord. 34, 1663–1671 (2019).
Acknowledgements
We gratefully acknowledge the excellent cooperation with many experts in the design and update of the Movement Disorder Society criteria for prodromal PD, which are an essential basis of this article.
Author information
Authors and Affiliations
Contributions
All authors researched evidence for the article, made substantial contributions to discussion of the content, contributed to writing of the article and reviewed and edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Neurology thanks C. Caig, A. Espay and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Berg, D., Borghammer, P., Fereshtehnejad, SM. et al. Prodromal Parkinson disease subtypes — key to understanding heterogeneity. Nat Rev Neurol 17, 349–361 (2021). https://doi.org/10.1038/s41582-021-00486-9
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41582-021-00486-9
This article is cited by
-
Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions
Nano Convergence (2024)
-
Cognitive training and promoting a healthy lifestyle for individuals with isolated REM sleep behavior disorder: study protocol of the delayed-start randomized controlled trial CogTrAiL-RBD
Trials (2024)
-
The pyroptosis mediated biomarker pattern: an emerging diagnostic approach for Parkinson’s disease
Cellular & Molecular Biology Letters (2024)
-
Integrating large-scale single-cell RNA sequencing in central nervous system disease using self-supervised contrastive learning
Communications Biology (2024)
-
Progression subtypes in Parkinson’s disease identified by a data-driven multi cohort analysis
npj Parkinson's Disease (2024)