28 Jun 2019

Parkinson’s disease inflicts brain damage years before patients begin shaking, slowing down, and feeling stiff. What happens before motor symptoms surface, however, remains murky. In a study in the June 19 Lancet Neurology, researchers led by Marios Politis, King’s College London, offer a glimpse into the brains of carriers of a PD-causing mutation, A53T SNCA, before they get sick. Using PET imaging, the scientists found reduced serotonin transporters in caudal areas of the brain in the absence of dopamine pathology, the hallmark of PD. In symptomatic carriers, serotonergic transporters had been lost in both caudal and rostral regions of the brain, and loss of dopamine transporters was now visible, too. Serotonergic loss in the brainstem correlated with motor and non-motor symptoms in both mutation carriers and in people with idiopathic PD.

Several news outlets have reported that the findings could lead to new ways of identifying people at risk for PD, confirm diagnoses, monitor disease progression, and aid the development and testing of drugs (e.g., June 19, 2019, The Guardian). However, Ole Isacson of Harvard Medical School's McLean Hospital, Belmont, Massachusetts, cautioned that the results are too limited in scope for that to happen just yet. “This is an important study, but I don’t think the data are generalizable. Parkinson’s disease caused by the A53T mutation is an extreme and very rare form of the disease,” Isacson said.

In 2003, based on examinations of postmortem brains, Heiko Braak proposed that Lewy bodies, abnormal deposits in the brains of people who died with PD, spread from caudal to rostral parts of the brain (Braak et al., 2003). From the brainstem, they extend into the midbrain, reaching the substantia nigra to trigger motor symptoms, before ultimately reaching the forebrain and neocortical regions.

Politis suspected serotonergic neurons might be early victims of PD. A main source of serotonergic transmission in the brain, the raphe nuclei, reside in the brainstem, and Politis and colleagues had found serotonin deficits in idiopathic PD patients before (Politis et al., 2010). Perhaps serotonergic pathology begins even before motor symptoms set in, he thought. “It has been on our minds for the last 10 years,” Politis said.

To find people they could be sure would develop Parkinson’s, first authors Heather Wilson, George Dervenoulas, and Gennaro Pagano recruited 14 carriers of the A53T SNCA mutation from movement disorders clinics in Athens, Greece, and Salerno, Italy. People with this mutation will almost certainly develop PD, and it induces similar symptoms to those of the most common, idiopathic form of PD, except more quickly. “It’s like a video on fast-forward,” said Politis.  

The researchers analyzed brain scans from seven A53T carriers without motor symptoms, and seven carriers already suffering from such symptoms. The average age of the premotor carriers was 42 and that of the symptomatic carriers 44. To ensure the former were truly free of motor abnormalities, the researchers asked them to wear wristband devices to monitor their movements continuously during seven days. “They did not have even mild symptoms,” said Politis. The researchers also examined 25 healthy, age-matched volunteers from London who responded to an advertisement to participate in the study.

The scientists used 11C-DASB, a PET tracer that binds serotonin transporters, 123I-FP-CIT, a SPECT marker that binds dopamine transporters, and an MRI scan onto which they mapped the PET and SPECT signals. Participants underwent all scans within three weeks of each other.

The dopaminergic signals in premotor carriers were similar to those of controls, confirming their motor health. In contrast, their serotonergic signals were, on average, 34 percent weaker in the raphe nuclei, and 22 percent weaker in the striatum. Losses also cropped up in the thalamus and amygdala (see image).

In symptomatic carriers, serotonergic loss amounted to 48 percent in the raphe nuclei and 57 percent in the striatum, and covered more rostral brain regions, including the hippocampus, cingulate, insula, and neocortical areas. On average, these patients had lost 71 percent of striatal dopamine transporters.

“These results conform with Braak’s staging hypothesis,” wrote Katharina Schindlbeck and David Eidelberg of the Feinstein Institute for Medical Research in Manhasset, New York, in an accompanying editorial (Schindlbeck and Eidelberg, 2019). 

In addition, the researchers examined 25 patients with idiopathic PD recruited from clinics in London. Consistent with previous studies, they had losses in both neurotransmitter systems. Looking for correlations between serotonergic pathology and PD symptoms, the researchers found that serotonergic pathology in the brainstem in particular correlated with both motor and non-motor symptoms as assessed by the MDS-UPDRS, a standardized scale of PD clinical progression. The correlation held in a second cohort of 40 PD patients who had been scanned independently, as well as in the A53T mutation carriers.

Comparing the sporadic to the mutation cases revealed that premotor carriers had lost about as much serotonin reuptake capacity as people with sporadic PD, while sick carriers had greater losses of both serotonin and dopamine transporters in the caudate. The authors suggested this points to similar pathological mechanisms, which are sped up in the A53T carriers.

To Isacson’s eye, however, the patterns of loss reflect differences, rather than commonalities, between the disease subtypes. As an example, he noted that the people with early idiopathic PD affecting only one side of the brain had robust, unilateral dopamine pathology, but little serotonin loss. If serotonin pathology always preceded dopamine pathology, one might expect the opposite. “There is no convergence. It is quite clear to me that this shows uniqueness of A53T carriers,” he said. Politis noted that it is difficult to draw conclusions from the relative size of the two pathologies because their rates of change and distributions are so different. Once dopamine loss starts, it barrels ahead faster than serotonin pathology, Politis said. Also, dopamine transporter loss occurs predominantly in the striatum and, in unilateral cases, mostly on one side of the brain, while serotonin loss is more widespread.

A study of serotonin in PD patients with mutations in another PD-associated gene, LRRK2, also tempers hopes about the generalizability of the new findings. Scientists led by Jon Stoessl, University of British Columbia, Vancouver, Canada, found that presymptomatic carriers of LRRK2 mutations sported increased, rather than decreased, serotonin transporter levels in the striatum, brainstem, and hypothalamus (Wile et al., 2017). Referring to the Politis study, Daryl Wile, first author of the Stoessl paper, said, “The study is fascinating because the results are quite different from those of the LRRK2 carriers. I see this as a step forward; it’s important to identify the early changes in different PD subtypes.” Wile thinks A53T may parallel sporadic PD more closely than LRRK2 does, but the jury is still out.

Longitudinal studies may help clear up these questions. Toward that end, Politis is making arrangements for the 14 mutation carriers to travel to London.

Could serotonin pathology serve as a biomarker for early detection and tracking of at least some forms of PD? Cost and availability of the required scanners pose problems, but Politis thinks that using longer-lived isotopes, for example, could make the procedure more accessible.—Marina Chicurel

Comments

1. • John Woulfe
     Ottawa Hospital
   • Posted: 28 Jun 2019

   This study complements growing appreciation for the involvement of non-dopaminergic, and extra-nigral, neural circuits in PD pathogenesis, and it extends this concept to early PD stages.

   By studying a cohort of patients with the A53T synuclein mutation, the authors convincingly link evidence for serotonergic dysfunction with synuclein dysfunction, a key pathophysiological player in the mechanisms underlying sporadic PD. Although the patient population is small, the results are convincing and invite further investigations into the involvement of serotonergic systems in PD at early disease stages. 

   Along these lines, there is considerable evidence that the enteric nervous system is involved in PD at the earliest disease stages. Serotonin plays an important role in enteric nervous system function. Future studies should examine whether serotonergic neurons in the ENS are materially involved in this early pathology. In addition to increasing the sample size, the impact of the findings would benefit from histopathological validation, particularly in relation to the Braak staging.

   View all comments by John Woulfe

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References

Paper Citations

1. Braak H, Del Tredici K, Rüb U, De Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. PubMed.
2. Politis M, Wu K, Loane C, Kiferle L, Molloy S, Brooks DJ, Piccini P. Staging of serotonergic dysfunction in Parkinson's disease: an in vivo 11C-DASB PET study. Neurobiol Dis. 2010 Oct;40(1):216-21. Epub 2010 May 31 PubMed.
3. Schindlbeck KA, Eidelberg D. Serotonergic pathology and Braak's staging hypothesis in Parkinson's disease. Lancet Neurol. 2019 Jun 19; PubMed.
4. Wile DJ, Agarwal PA, Schulzer M, Mak E, Dinelle K, Shahinfard E, Vafai N, Hasegawa K, Zhang J, McKenzie J, Neilson N, Strongosky A, Uitti RJ, Guttman M, Zabetian CP, Ding YS, Adam M, Aasly J, Wszolek ZK, Farrer M, Sossi V, Stoessl AJ. Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies. Lancet Neurol. 2017 May;16(5):351-359. Epub 2017 Mar 20 PubMed.

External Citations

1. The Guardian

Further Reading

Papers

1. Helmich RC, Vaillancourt DE, Brooks DJ. The Future of Brain Imaging in Parkinson's Disease. J Parkinsons Dis. 2018;8(s1):S47-S51. PubMed.