26 Mar 2014

The hunt continues for harbingers of Parkinson’s disease that may one day allow patients to be treated before symptoms take hold. A Keystone conference called “Parkinson’s Disease: Genetics, Mechanisms, and Therapeutics,” held 2-7 March in Keystone, Colorado, revealed that progress has been slow. No new reliable markers have surfaced, though researchers have recruited presymptomatic individuals considered at high risk for the disease to search for preclinical markers in an early version of the Parkinson’s Progression Markers Initiative (PPMI). Others continue to pursue diagnostic blood tests, which have proven hard to find for many neurodegenerative diseases.   

“We need PD biomarkers to facilitate new models for drug design that would help us understand the earliest pathology in disease,” said Kenneth Marek of the Institute for Neurodegenerative Disorders in New Haven, Connecticut. “With these biomarkers, ultimately, we could identify groups prior to the onset of symptoms and treat them with drugs that could prevent disease.” Marek also noted that the biomarkers could serve as key measures of disease modification in response to therapy. 

Marek kicked off the biomarkers session at Keystone by describing an expansion of PPMI. Started three years ago, the initiative spans 24 study sites in the United States, Europe, and Israel. The study’s 400 newly diagnosed PD patients and 200 controls undergo extensive brain imaging and regularly donate CSF and blood samples. The hope is that biological monitoring will reveal biomarkers that correlate with disease progression. Early data from the cohort revealed that the PD patients had lower levels of α-synuclein, tau, and phosphorylated tau in the CSF (see Sep 2013 news story). While the patients enrolled in PPMI are in the earliest stages of PD, Marek is in search of prodromal markers. “We wanted to move back in time and see if we could enroll asymptomatic people at risk for disease,” Marek told Alzforum. “The challenge is, how do you find these people?”

Marek laid out his strategy for adding another P, for prodromal, to the PPMI cohort. To find patients who fit the bill, he is taking advantage of two early symptoms that often precede the onset of PD: loss of the sense of smell and a sleep disorder called REM Behavior Disorder (RBD), in which people physically act out dreams, kicking and sometimes even falling out of bed (see Aug and Sep 2010 news stories). Recruited via scratch-and-sniff tests sent in the mail and outreach events, respectively, patients positive for either of these predictors will undergo brain imaging for deficits in dopamine transporter (DAT). Using these three combined measures, Marek hopes to recruit patients who are likely to develop PD symptoms within two to five years. The prodromal PPMI is slated to recruit 100 such patients, and so far has found about 20, Marek said.

Another cohort to be included in PPPMI is people who carry mutations in LRRK2 and α-synuclein (SNCA). Because fewer than 2 percent of PD patients have the most common LRRK2 mutation, G2019S, Marek and colleagues are reaching out to the Ashkenazi Jewish population, in whom the frequency is 15 percent of those with the disease. Focusing the search to areas such as Boca Raton, Florida, where many older Ashkenazi Jews live, has boosted recruitment, Marek said. For the even rarer SNCA mutations, Marek is looking to Greek and Southern Italian populations, which harbor higher rates.

Other researchers anticipated future discoveries to come out of the prodromal PPMI cohort. “The ‘triple-P MI’ is very exciting,” said Alice Chen-Plotkin of the University of Pennsylvania in Philadelphia. Once the cohort is fully assembled, she hopes to test blood samples for biomarker candidates she has identified in discovery screens.

Chen-Plotkin believes she can find PD biomarkers in the blood, a goal other researchers consider lofty. Most think the CSF is likelier to contain such markers. However, Chen-Plotkin said that barriers to CSF collection still exist in clinical settings. Trained staff must collect the sample, and some patients are uncomfortable with undergoing lumbar punctures, especially on a regular basis. “Developing a blood-based marker may be harder in some ways than finding one in CSF, but if you are successful, the ability to translate it widely and quickly is so high that it’s worth looking,” said Chen-Plotkin, who works as both a researcher and a physician.

Chen-Plotkin employed multiplex assays to screen the blood of PD patients and controls for more than 100 different proteins, looking for associations with other factors related to disease progression, such as the age of onset or the severity of cognitive decline. She had previously found that PD patients with low cognitive scores tended to have lower levels of epidermal growth factor (EGF) in their blood, and that patients with lower levels of ApoA1 had an earlier age of onset and more severe symptoms (see Qiang et al., 2013, and Chen-Plotkin et al., 2011). She said she and others have since replicated these results in different cohorts. Chen-Plotkin’s group screened the blood of patients enrolled in the Parkinson’s Associated Risk study (PARS), a precursor to the prodromal PPMI study. In this cohort, she found that a higher dopaminergic transporter signal on DAT scans correlated with higher plasma levels of ApoA1. Interestingly, a Taiwanese and U.S. study reported lower incidence of PD in people taking cholesterol-lowering statins, which can raise ApoA1 levels (see Lee et al., 2013, and Gao et al., 2012). If studies were to show that low levels of ApoA1 hasten the onset of PD, it would become possible to treat patients with ApoA1-boosting drugs to stave off disease, but such a strategy is a still a long way down the road, Chen-Plotkin said.

Other researchers cautioned that finding biomarkers in blood would be difficult. “Blood-based markers have been elusive,” said Thomas Montine of the University of Washington, Seattle, “Lots of people have tried, but it looks like Chen-Plotkin is getting some traction.

In his talk, Montine focused on markers of oxidative damage.  For decades, researchers have explored links between oxidative stress and neurodegeneration, but they have not answered the question of whether oxidative stress precedes disease or hastens its arrival. Montine and colleagues screened CSF samples from 320 healthy people aged 21 to 100 for the oxidative damage marker isoprostane. Levels of the protein increased with age, but it correlated more strongly with lifestyle factors such as smoking, body-mass index, and diet, than aging alone.  Interestingly, people who ate a low-fat diet for a month managed to reduce their CSF levels of isoprostane.

Attendees wondered whether isoprostane was an early indicator of latent disease, or just a marker of aging.  “We can’t yet say how important this type of injury is to age-related susceptibility to AD or PD,” Montine told Alzforum. “But our data suggests that there are lifestyle changes that are associated with having less of this type of injury. Presumably that’s a good thing, and it could make the brain less permissive to these diseases.”—Jessica Shugart

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References

News Citations

1. Fluid Biomarkers Give Clues to Disease Progression in Parkinson’s 4 Sep 2013
2. Paralysis Lost: Acting-Out Dreams Precede Parkinson’s Dementia 6 Aug 2010
3. Bad Dream—Sleep Disorder Plus Neuroimaging Markers Spell Trouble 24 Sep 2010

Paper Citations

1. Qiang JK, Wong YC, Siderowf A, Hurtig HI, Xie SX, Lee VM, Trojanowski JQ, Yearout D, B Leverenz J, Montine TJ, Stern M, Mendick S, Jennings D, Zabetian C, Marek K, Chen-Plotkin AS. Plasma apolipoprotein A1 as a biomarker for Parkinson disease. Ann Neurol. 2013 Jul;74(1):119-27. Epub 2013 Aug 6 PubMed.
2. Chen-Plotkin AS, Hu WT, Siderowf A, Weintraub D, Goldmann Gross R, Hurtig HI, Xie SX, Arnold SE, Grossman M, Clark CM, Shaw LM, McCluskey L, Elman L, Van Deerlin VM, Lee VM, Soares H, Trojanowski JQ. Plasma epidermal growth factor levels predict cognitive decline in Parkinson disease. Ann Neurol. 2011 Apr;69(4):655-63. Epub 2010 Nov 29 PubMed.
3. Lee YC, Lin CH, Wu RM, Lin MS, Lin JW, Chang CH, Lai MS. Discontinuation of statin therapy associates with Parkinson disease: a population-based study. Neurology. 2013 Jul 30;81(5):410-6. Epub 2013 Jul 24 PubMed.
4. Gao X, Simon KC, Schwarzschild MA, Ascherio A. Prospective study of statin use and risk of Parkinson disease. Arch Neurol. 2012 Mar;69(3):380-4. PubMed.

External Citations

1. PPMI
2. PARS

Further Reading

Papers

1. Chahine LM, Stern MB, Chen-Plotkin A. Blood-based biomarkers for Parkinson's disease. Parkinsonism Relat Disord. 2014 Jan;20 Suppl 1:S99-103. PubMed.