When a German anatomist first proposed in 2003 that Parkinson’s disease (PD) begins in the gut, then slowly makes its way to the brain and spreads to different regions, his idea might have sounded like fiction. But when he and a collaborator then added that a pathogen, possibly a virus, sneaks its way into the nervous system simultaneously from the nose and gut to set off the disease process, the hypothesis became downright fantastic. After all, conventional wisdom viewed Parkinson’s as degeneration of the substantia nigra, that black-pigmented sliver of the brain. But less than a decade later, the hypothesis is gaining ground, as ongoing studies provide clues in its support. If successful, these new investigations could upend long-held views about how Parkinson’s develops.

In the past decade, neuroanatomists Heiko Braak and Kelly Del Tredici, both currently at the University of Ulm in Germany, published a series of papers describing the distribution of Lewy bodies—those protein aggregates that are the hallmarks of the pathology of PD—in the central and peripheral nervous systems of deceased patients. To detect these lesions, they used an antibody to α-synuclein, the main protein component of these aggregates. α-synuclein is a normal protein found in many types of nerve cells, but something about the disease process of PD causes the protein to misfold and, as a result, clump together inside the cells.

Based on painstaking observations of hundreds of tissue samples, Braak and colleagues initially proposed that the α-synuclein pathology progresses in predictable stages defined by its distribution. The pathology advances from the peripheral nervous system to the brainstem, and from there upward to the midbrain and to higher brain regions, following paths laid out by connecting neurons. This staging system resonates with that described previously by Braak and colleagues for Alzheimer’s disease (Braak and Braak, 1991 and online seminar by H. Braak).




The pathology associated with Parkinson’s disease progresses from the peripheral nervous system to the brainstem, and from there it advances to the midbrain and higher brain regions. Image credit: H. Braak and K. Del Tredici

“The breakthrough in the field was that they proposed that the process starts nowhere near the substantia nigra,” says John Duda of the Philadelphia Veteran’s Affairs Medical Center. Up until then the substantia nigra, located in the midbrain or mesencephalon, had been the main focus of PD research. The motor symptoms that constitute the diagnosis of the disease—tremor, rigidity, slowness of movement or instability while standing up—are thought to result from the loss of dopamine-producing brain cells in this region and subsequent lack of transmitter input into the striatum, an important motor control area. Current medicines for PD typically consist of the dopamine precursor levodopa and dopamine agonists, but these treatments lose effectiveness over time.

Despite the focus on the substantia nigra, most PD patients have additional, non-motor symptoms, and PD is coming to be understood as a much broader disease. Chronic constipation, loss of smell, and REM sleep disorders often occur before the motor problems (O’Sullivan et al., 2008 and ARF related news story). A large epidemiological study, the Honolulu-Asia Aging Study, showed that men who reported less frequent bowel movements had a significantly higher risk of developing PD within the next 24 years (Abbott et al., 2001; Abbott et al., 2003).

One of the attractive features of Braak’s staging scheme is that the areas of the nervous system littered with Lewy bodies at the earliest stages of disease could account for these non-motor symptoms. The staging system, wrote Braak in an e-mail to ARF, “has drawn attention to the damage in other transmitter systems—in other words, apart from and before the nigrostriatal system. In addition, it can serve as a framework for relating the pathology in other parts of the nervous system (gastrointestinal tract, spinal cord, and so on) to that in the brain.”

What the Data Show
In their first paper in 2003 (Braak et al., 2003), Braak, Del Tredici, and colleagues examined postmortem tissues from 168 autopsied patients belonging to one of three groups: 41 patients had been diagnosed with sporadic PD; 69 had no clinical symptoms of PD but had Lewy bodies in their brains; and 58 people had no PD and no evidence of Lewy bodies. Whereas most pathologists use tissue sections that are, at most, 10 microns thick, Braak and colleagues developed a new technique using 100 micron-thick sections, allowing them to visualize pathology over large distances, so that they would not miss any changes that would escape detection in a thinner sample. “Braak is a hugely gifted pathologist,” says Michael Schlossmacher, a neurologist at the University of Ottawa in Canada, echoing a sentiment expressed by most researchers in the field.

Using this technique, Braak and colleagues found that, in samples with mild pathology, which Braak called Stage 1, the Lewy bodies are typically confined to the olfactory bulb and the dorsal motor nucleus of the vagus nerve. Because the vagus nerve connects the brain to the enteric nervous system (ENS), the authors proposed that the disease could start in the gut and move along the vagus nerve in an upstream, or retrograde, direction toward the brain. In Stage 2, Lewy bodies continue to ascend into the brainstem, reaching the medulla oblongata and pontine tegmentum, parts of the brainstem that control swallowing, sleep, and other autonomic functions sometimes affected in PD. By Stage 3, pathology starts to show up in the amygdala (an almond-shaped mass of neurons involved in processing fear and other emotions, but also the sense of smell) and in the infamous substantia nigra; this is the stage when the motor phase of the disorder begins. In Stage 4, pathology in areas affected in earlier stages worsens, and Lewy bodies progress to the forebrain and encroach on a portion of the cerebral cortex (the temporal mesocortex), whereas the neocortex, the part of the brain involved in higher functions, remains unaffected. In Stages 5 and 6, the pathology is full blown, appearing initially in the anterior association and prefrontal areas of the neocortex and then spreading to the posterior association areas, which are involved with memory and learning, and planning movement. Defects in these areas could explain many of the cognitive problems associated with advanced PD. “There is no evidence in our material for involvement of the cerebral cortex in the absence of lesions in the brainstem,” reads their 2003 paper published in the Neurobiology of Aging, essentially making the point that pathology rises up from lower to higher regions of the brain as PD gets worse.

In a subsequent study, Braak applied his pathology skills to the enteric nervous system (ENS). Earlier work had indicated that Lewy bodies could be detected in the ENS, but those studies had gone largely ignored. “The [sporadic] sPD-associated involvement of the ENS initially reported two decades ago found relatively little resonance in comparison to the literature devoted to lesions in the CNS,” reads their 2006 paper published in Neuroscience Letters (Braak et al., 2006). Braak and colleagues examined five autopsy patients who had Lewy bodies in the CNS—three had been diagnosed with PD and two had no clinical symptoms of the disease. In all five patients, Braak and colleagues found Lewy bodies in both the Meissner’s and Auerbach’s plexus, the two layers that make up the ENS.

Because the ENS lesions were found both in PD cases and in asymptomatic individuals who only had Lewy bodies in the lower brainstem, the results confirmed the authors’ view that the disease could start off in the ENS. But Braak and colleagues went further to postulate that the disease could be set off by a yet-unidentified pathogen in the gut (Braak et al., 2003). Then, Braak and Christopher Hawkes, a neurologist now at Barts and The London School of Medicine and Dentistry, U.K., revised this hypothesis to suggest that the pathogen could simultaneously enter the nose, by inhalation, and the gut, by swallowing nasal secretions, and then progress to the brain from two directions, providing a “dual-hit” (Hawkes et al., 2009).

Although Hawkes personally favors the explanation that the causative pathogen is a virus, he said it could also be a toxin, bacteria, or any inflammatory agent that causes α-synuclein to misfold and aggregate. Although Lewy bodies have not been found in nasal passages, the olfactory bulb is chock full of these lesions. From there, they could reach the amygdala in the temporal lobe of the brain through forward, or anterograde, motion, hopping across synapses of connecting neurons. At the same time, the pathology starting in the gut would move in a retrograde direction up the motor vagus nerve fibers, reaching the brainstem and then progressing to the amygdala and substantia nigra in Stage 3 of the disease. “These two paths meet up in the temporal lobe of the brain,” said Hawkes. “By that time, the patient is quite ill.”

Although Braak and colleagues did not assign a time course to the spread of disease, the process could take several decades to occur.

Not Everyone Agrees on the Interpretation
While most researchers agree that α-synuclein pathology can be found in many regions of the brain, many have disagreed with Braak’s proposed staging sequence, saying that it does not apply to all patients and questioning its clinical relevance. In addition, certain aspects of the hypothesis, such as its viral origin or its spread, remain speculative. The danger is that “this idea has had a profound effect on how experimentalists are approaching the disease and which animal models they think are the best,” Robert Burke, a pathologist at Columbia University in New York City told ARF.

Others, however, say that, although there may be exceptions to the staging system and some of the details of the hypothesis may be wrong, the scheme as a whole is benefiting the field. “The dopaminergic research has not been going anywhere for some time now,” said Schlossmacher. “We have to do something different, and Braak made us think outside the box.” The value of Braak’s hypothesis, say supporters, is that it has provided new ideas for them to test. “There are many who strongly support the hypothesis and others who question it. For me, the Braak hypothesis has been a major source of inspiration for asking lots of interesting questions in animals and other experimental models,” said Patrik Brundin of Lund University in Sweden. “Research is about putting forward hypotheses and then testing them.”

Part 2 and Part 3 of this series highlight the main points of contention raised by Braak’s staging scheme and the new line of investigations the hypothesis has inspired.—Laura Bonetta.

This is Part 1 of a three-part series. See also Part 2 and Part 3. Read the entire series.

Laura Bonetta is a freelance writer in Garrett Park, Maryland.


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  1. This is a useful and important paper on the experimental findings to support Braak's hypothesis, which has provided new ideas for researchers to test the role of functional tracts and brain structure in Alzheimer's disease, including Lewy bodies in the olfactory bulb and the dorsal motor nucleus of the vagus nerve connecting to the enteric nervous system (ENS). It also introduces a causative pathogen (virus, toxin, bacteria, or any inflammatory agent), which can cause α-synuclein to misfold and aggregate, and be subsequently associated with AD symptoms.

    The Braak hypothesis has been a major source of inspiration for further experimental studies. More and more recent studies have supported or contradicted the hypotheses: the review by Hawkes et al. (2007) on "Parkinson's disease—a dual-hit hypothesis"; the study by Kingsbury et al. (2010) supported the Braak hypothesis of caudorostral development, but indicated that the extent of the disease in the cortex and the severity of pathology in the medulla were independent of one another; the study by Logue et al. (2011) on magnetic resonance imaging-measured atrophy and its relationship to cognitive functioning in vascular dementia; and the test by Takeda et al. (2009) on metabolic changes in the amygdala.


    . Parkinson's disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol. 2007 Dec;33(6) Epub 2007 Oct 24 PubMed.

    . Brain stem pathology in Parkinson's disease: an evaluation of the Braak staging model. Mov Disord. 2010 Nov 15;25(15):2508-15. PubMed.

    . Magnetic resonance imaging-measured atrophy and its relationship to cognitive functioning in vascular dementia and Alzheimer's disease patients. Alzheimers Dement. 2011 Sep;7(5):493-500. PubMed.

    . [Pathophysiological process underlying Parkinson's disease: motor & non-motor symptoms]. Rinsho Shinkeigaku. 2009 Nov;49(11):888-9. PubMed.

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News Citations

  1. Blunted Sense of Smell Parallels Pathology in AD, PD
  2. Parkinson's: It Started With a Gut Feeling
  3. Parkinson's: An Unlikely Proposal Gains Momentum

Paper Citations

  1. . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. PubMed.
  2. . Nonmotor symptoms as presenting complaints in Parkinson's disease: a clinicopathological study. Mov Disord. 2008 Jan;23(1):101-6. PubMed.
  3. . Frequency of bowel movements and the future risk of Parkinson's disease. Neurology. 2001 Aug 14;57(3):456-62. PubMed.
  4. . Environmental, life-style, and physical precursors of clinical Parkinson's disease: recent findings from the Honolulu-Asia Aging Study. J Neurol. 2003 Oct;250 Suppl 3:III30-9. PubMed.
  5. . Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. PubMed.
  6. . Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett. 2006 Mar 20;396(1):67-72. PubMed.
  7. . Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm. 2003 May;110(5):517-36. PubMed.
  8. . Parkinson's disease: the dual hit theory revisited. Ann N Y Acad Sci. 2009 Jul;1170:615-22. PubMed.

Other Citations

  1. online seminar by H. Braak

Further Reading


  1. Blunted Sense of Smell Parallels Pathology in AD, PD