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Exploring Braak’s Hypothesis of Parkinson’s Disease
Open accessAbstract
Parkinson’s disease (PD) is a neurodegenerative disorder for which there is no cure. Most patients suffer from sporadic PD, which is likely caused by a combination of genetic and environmental factors. Braak’s hypothesis states that sporadic PD is caused by a pathogen that enters the body via the nasal cavity, and subsequently is swallowed and reaches the gut, initiating Lewy pathology (LP) in the nose and the digestive tract. A staging system describing the spread of LP from the peripheral to the central nervous system was also postulated by the same research group. There has been criticism to the Braak’s hypothesis, in part because not all patients follow the proposed staging system. Here, we review literature that either supports or criticizes the Braak’s hypothesis, focused on the enteric route, digestive problems in patients, the spread of LP on a tissue and a cellular level, and the toxicity of the protein αSynuclein (αSyn), which is the major constituent of LP. We conclude that the Braak’s hypothesis is supported by in vitro, in vivo and clinical evidence. However, we also conclude that the staging system of Braak only describes a specific subset of patients with young onset and long duration of the disease.
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“GI symptoms may predate motor features by years, consistent with the concept that α-synuclein pathology can involve the ENS and vagal/brainstem autonomic nuclei early in disease (Rietdijk et al., 2017; Travagli et al., 2020).”
From Autonomic nervous system and gastrointestinal manifestations with an emphasis on gastric dysfunction (2026) · cites this paper as Rietdijk et al., 2017
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“In accordance with the Braak hypothesis (25) that a pathogen reaching the gut initiates pathology that spreads to the CNS in Parkinson disease, neuropathologic studies showed accumulation of abnormal inclusions containing α -sy- nuclein (Lewy neurites) in the ENS, dorsal motor nucleus of the vagus…”
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“It is predominantly associated with the irreversible degeneration of dopaminergic neurons in the substantia nigra and other brain regions [4], often characterised by widespread Lewy body (LB) formation in the central and peripheral nervous systems.”
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Natale, G., Limanaqi, F., Busceti, C. L., Mastroiacovo, F., Nicoletti, F., Puglisi‐Allegra, S., & Fornai, F. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.639140 · Cited by 116
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Pardo-Moreno, T., García‐Morales, V., Suleiman‐Martos, N., Rivas-Domínguez, A., Mohamed-Mohamed, H., Ramos‐Rodríguez, J. J., Melguizo‐Rodríguez, L., & González‐Acedo, A. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15030770 · Cited by 116
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“One of the most widely accepted frameworks to describe the spread of sporadic PD is Braak’s hypothesis, which suggests that PD progresses through six different stages, gradually evolving from the lower brain stem to the neocortex (Rietdijk et al., 2017).”
BackgroundParkinson’s Disease and the Gut: Symptoms, Nutrition, and Microbiota
Yemula, N., Dietrich, C. M., Dostal, V., & Hornberger, M. (2021) · Journal of Parkinson s Disease · doi:10.3233/jpd-212707 · Cited by 71
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Dias-Carvalho, A., Sá, S. I., Carvalho, F., Fernandes, E., & Costa, V. M. (2024) · Archives of Toxicology · doi:10.1007/s00204-023-03628-8 · Cited by 60
“From there, the misfolded α-synuclein aggregates and spreads toward the CNS via the olfactory tract or the vagal nerve (Rietdijk et al. 2017).”
BackgroundAre We What We Eat? Impact of Diet on the Gut–Brain Axis in Parkinson’s Disease
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“…stress; Mitochondria; Neuroinflammation; Vulnerability Introduction Progressive pathological staging and degeneration in Parkinson’s disease (PD) occur along a caudo-rostral axis, especially for patients with young onset and long duration of the disease (Braak et al., 2003; Rietdijk et al., 2017).”
BackgroundPathological and Therapeutic Advances in Parkinson’s Disease: Mitochondria in the Interplay
Naren, P., Cholkar, A., Kamble, S., Khan, S. S., Srivastava, S., Madan, J., Mehra, N. K., Tiwari, V., Singh, S. B., & Khatri, D. K. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220682 · Cited by 60
“The symptomatology-based staging of disease progression as per Braak’s observation states that at early stage (stages 1 and 2- involving lewy neurite formation in lower brain stem and medulla oblangata) the non-motor symptoms are noted in clinical cases while the motor symptoms are visible at intermediate stage (stage…”
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“According to Braak’s hypothesis, pathogens enter the oral and nasal cavities and initiate the formation of Lewy bodies, resulting in sporadic PD [39].”
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“Moreover, according to Braak’s hypothesis, sporadic PD is caused by a bunch of pathogens that enter the body through the nasal cavity and reaches the gut that ultimately initiates Lewy pathology in the nose and digestive tract, and thus, demonstrates the potential relationship between gut microbiota and PD progression…”
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Microbes Tickling Your Tummy: the Importance of the Gut-Brain Axis in Parkinson’s Disease
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Dolatshahi, M., Sabahi, M., & Aarabi, M. H. (2021) · Molecular Neurobiology · doi:10.1007/s12035-020-02236-2 · Cited by 51
Neuropathology of Nonmotor Symptoms of Parkinson's Disease
Jellinger, K. A. (2017) · International review of neurobiology · doi:10.1016/bs.irn.2017.05.005 · Cited by 50
Scholefield, M., Church, S. J., Xu, J., Patassini, S., Hooper, N. M., Unwin, R. D., & Cooper, G. J. S. (2021) · Metabolites · doi:10.3390/metabo11090569 · Cited by 47
Clinical and diagnostic implications of Alzheimer's disease copathology in Lewy body disease
Barba, L., Abu‐Rumeileh, S., Barthel, H., Massa, F., Foschi, M., Bellomo, G., Gaetani, L., Thal, D. R., Parnetti, L., & Otto, M. (2024) · Brain · doi:10.1093/brain/awae203 · Cited by 52
Pathogenesis‐targeted therapeutic strategies in Parkinson's disease
Jankovic, J. J. (2018) · Movement Disorders · doi:10.1002/mds.27534 · Cited by 47
Data-driven evolution of neurosurgical gene therapy delivery in Parkinson’s disease
Richardson, R. M., Bankiewicz, K. S., Christine, C. W., Laar, A. D. V., Gross, R. E., Lonser, R. R., Factor, S. A., Kostyk, S. K., Kells, A. P., Ravina, B. M., et al. (2020) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2020-322904 · Cited by 48
“1 Although PD pathology is known to be complex, 2 the idea of counteracting or reversing pathology in the nigrostriatal dopamine circuit has been a focus of the translational neuroscience field since the early 1980s.”
BackgroundRenner, H., Schöler, H. R., & Bruder, J. M. (2021) · Movement Disorders · doi:10.1002/mds.28775 · Cited by 47
“28,29 30-32 The long time spans of PD progression before diagnosis make it dif fi cult to understand and emulate the cumulative effects of age and environment in lab settings and to narrow down all the possible factors involved.”
BackgroundWhat Is the Evidence that Parkinson’s Disease Is a Prion Disorder, Which Originates in the Gut?
Kujawska, M., & Jodynis‐Liebert, J. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113573 · Cited by 48
Spreading of alpha‐synuclein – relevant or epiphenomenon?
Killinger, B. A., & Kordower, J. H. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14779 · Cited by 46
Laurencin, C., Lancelot, S., Brosse, S., Mérida, I., Redouté, J., Greusard, E., Lamberet, L., Liotier, V., Bars, D. L., Costes, N., et al. (2023) · Brain · doi:10.1093/brain/awad338 · Cited by 46
Jeon, H., Bae, C., Lee, Y., Kim, H.-Y., & Kim, S. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.02.028 · Cited by 45
Yang, C., Wang, W., Deng, P., Li, C., Zhao, L., & Gao, H. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.778527 · Cited by 43
The impact of device-assisted therapies on the gut microbiome in Parkinson’s disease
Lubomski, M., Xu, X., Holmes, A. J., Yang, J. Y. H., Sue, C. M., & Davis, R. L. (2021) · Journal of Neurology · doi:10.1007/s00415-021-10657-9 · Cited by 43
NLRP3 and Infections: β-Amyloid in Inflammasome beyond Neurodegeneration
Sita, G., Graziosi, A., Hrelia, P., & Morroni, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136984 · Cited by 43
Microbiome-based therapies for Parkinson’s disease
Alam, M., Abbas, K., Mustafa, M., Usmani, N., & Habib, S. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1496616 · Cited by 46
Gray Matter Volume Loss in Proposed Brain‐First and Body‐First Parkinson's Disease Subtypes
Banwinkler, M., Dzialas, V., Initiative, T. P. P. M., Hoenig, M. C., & van Eimeren, T. (2022) · Movement Disorders · doi:10.1002/mds.29172 · Cited by 40
“Yet recent evidence suggested that this staging scheme may not sufficiently account for the observed interindividual heterogeneity in the pathophysiological progression of PD.(5,6) Interestingly, a recently introduced hypothesis postulates two contrasting subtypes of α-SN spread based on the anatomic location of initi…”
BackgroundInfluentialLópez‐Pingarrón, L., Almeida, H., Soria-Aznar, M., Reyes-Gonzales, M. C., Rodríguez-Moratinos, A. B., Muñoz‐Hoyos, A., & García, J. J. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45040232 · Cited by 40
West, C. L., Mao, Y., Delungahawatta, T., Amin, J. Y., Farhin, S., McQuade, R. M., Diwakarla, S., Pustovit, R. V., Stanisz, A. M., Bienenstock, J., et al. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-202076 · Cited by 42
“According to Braak’s hypothesis PD may begin peripherally with the development of misfolded (cid:2) - syn aggregates (Lewy bodies) in the olfactory nerves, submandibular gland and ENS [4, 5], then traffic to the CNS.”
Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease
Долгачева, Л. П., Зинченко, В. П., & Goncharov, N. V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113043 · Cited by 43
Capelle, C., Ciré, S., Hedin, F., Hansen, M., Pavelka, L., Grzyb, K., Kyriakis, D., Hunewald, O. E., Konstantinou, M., Revets, D., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-43053-0 · Cited by 46
“It has been postulated that PD pathology might arise in the periphery and migrate to the CNS via the vagus nerve 82,83 .”
BackgroundChiu, L. S., & Anderton, R. S. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15892 · Cited by 36
“Thus, dysbiosis of the gut microbiome and their metabolites can contribute to colonic pro-inflammatory cytokine production which may drive αSyn aggregation and influence PD progression and severity (Gorecki et al., 2020; Houser & Tansey, 2017; Rietdijk et al., 2017).”
BackgroundGut-brain axis: gut dysbiosis and psychiatric disorders in Alzheimer’s and Parkinson’s disease
Denman, C. R., Park, S. M., & Jo, J. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1268419 · Cited by 45
“Although tau may not align with Braak’s hypothesis in the same manner as Aβ and α-syn, the potential role of GBA in AD and PD has attracted significant attention (Rietdijk et al., 2017).”
BackgroundCOVID-19 and Parkinson’s Disease: Are We Dealing with Short-term Impacts or Something Worse?
Victorino, D. B., Guimarães‐Marques, M., Nejm, M. B., Scorza, F. A., & Scorza, C. A. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-202073 · Cited by 37
A secret that underlies Parkinson's disease: The damaging cycle
Sun, F., Deng, Y., Han, X., Liu, Q., Zhang, P., Manzoor, R., & Ma, H. (2019) · Neurochemistry International · doi:10.1016/j.neuint.2019.104484 · Cited by 37
The neuromicrobiology of Parkinson’s disease: A unifying theory
Muñoz, M., Empadinhas, N., & Cardoso, S. M. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101396 · Cited by 38
“Also, by excluding patients with LB pathology in higher brain regions but not in the DMV (Kalaitzakis et al., 2008; Rietdijk et al., 2017), a subset of PD patients was not included.”
BackgroundResultThangaleela, S., Sivamaruthi, B. S., Kesika, P., Bharathi, M., & Chaiyasut, C. (2022) · Microorganisms · doi:10.3390/microorganisms10081544 · Cited by 37
“Advanced” Parkinson's disease: A review
Aslam, S., Manfredsson, F. P., Stokes, A. M., & Shill, H. A. (2024) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2024.106065 · Cited by 38
Potential Crosstalk Between Parkinson's Disease and Energy Metabolism
Liu, M., Jiao, Q., Du, X., Bi, M., Chen, X., & Jiang, H. F. (2021) · Aging and Disease · doi:10.14336/ad.2021.0422 · Cited by 34
The emerging role of microbiota derived SCFAs in neurodegenerative disorders
Wachamo, S., & Gaultier, A. (2025) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2025.101012 · Cited by 36
“Subsequent in vitro , in vivo , and clinical studies have corroborated Braak ’ s hypothesis (Rietdijk et al., 2017).”
Brain-gut-microbiota axis in Parkinson’s disease: A historical review and future perspective
Dong, S., Sun, M., He, C. H., & Cheng, H. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.02.015 · Cited by 32
Good bacteria, oxidative stress and neurological disorders: Possible therapeutical considerations
Soheili, M., Alinaghipour, A., & Salami, M. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.120605 · Cited by 33
Sex and Brain: The Role of Sex Chromosomes and Hormones in Brain Development and Parkinson’s Disease
Terrin, F., Tesoriere, A., Plotegher, N., & Valle, L. D. (2023) · Cells · doi:10.3390/cells12111486 · Cited by 32
“Finally, this protein, likely in its aggregated forms, is involved in the spreading of the pathology across the body and different brain regions according to the Braak hypothesis [127], which would explain disease progression.”
Uncoupling the roles of firing rates and spike bursts in shaping the STN-GPe beta band oscillations
Bahuguna, J., Sahasranamam, A., & Kumar, A. (2020) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1007748 · Cited by 32
Pallàs, M., Vázquez, S., Sanfeliu, C., Galdeano, C., & Griñán‐Ferré, C. (2020) · Biomolecules · doi:10.3390/biom10050703 · Cited by 33
Metadata
- Authors
- Rietdijk, C. D., Perez-Pardo, P., Garssen, J., van Wezel, R. J. A., & Kraneveld, A. D.
- Affiliations
- Utrecht University (NL)
- Corresponding author
- Kraneveld, Aletta D.
- Venue
- Frontiers in Neurology
- Publisher
- Frontiers Media SA
- Published
- 2017-02-13
- Volume
- 8
- Pages
- 37-37
- ISSN
- 1664-2295 (ISSN-L)
- PMC
- PMC5304413
- OpenAlex
- W2588841770
- Cited by
- 395
- References
- 153
- Citations by year
- 2026: 41 · 2025: 56 · 2024: 65 · 2023: 43 · 2022: 50 · 2021: 50 · 2020: 30 · 2019: 32 · 2018: 18 · 2017: 10
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Neurology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Twente Research Information (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Parkinson's disease, Braak hypothesis, Lewy body pathology, sporadic Parkinson's disease, gut-brain axis, alpha-synuclein toxicity, Lewy bodies, neurodegeneration, early-onset Parkinson's disease
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