Blood Biomarkers Identified for Cognitive Changes With Parkinson’s

Levels of vesicles carrying disease-linked proteins seen to distinguish patients

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by Steve Bryson, PhD |

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Blood levels of small vesicles originating in neurons and containing proteins related to Parkinson’s disease or Alzheimer’s disease — alpha-synuclein, phosphorylated tau, or insulin receptor substrate 1 (IRS-1) — can be biomarkers of cognitive impairment in Parkinson’s patients, a study reported.

Changes in the levels of vesicles carrying these proteins distinguished people with Parkinson’s from those without the disease. Importantly, they also spotted patients with cognitive problems or dementia from among all with Parkinson’s.

“Blood biomarkers that help detect cognitive impairment in Parkinson’s could improve timely diagnosis and treatment. Future studies may measure extracellular vesicle biomarkers over time to establish a timeline for biomarker changes in people with Parkinson’s,” the National Institute on Aging, which partly funded the study, stated in a press release.

The study, “Extracellular vesicle biomarkers for cognitive impairment in Parkinson’s disease,” was published in the journal Brain.

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Changes in cognition can be common with Parkinson’s disease

In addition to classic motor symptoms, people with Parkinson’s experience problems with thinking and memory, known as cognitive impairment. Because of the wide variability of cognitive symptoms, it is essential to identify biomarkers to diagnose these patients and predict likely outcomes accurately.

Extracellular vesicles (EVs) are tiny, membrane-bound sacs released by most cells in the body, including neurons, that carry molecular cargo such as proteins and RNA to help coordinate cell-to-cell communication.

Evidence suggests that EVs can also carry disease-related molecules, including clumps of the protein alpha-synuclein that accumulate and damage brain cells in Parkinson’s.

A team of researchers at the National Institute on Aging and the New Zealand Brain Research Institute examined whether the blood levels of neuron-released EVs could distinguish between people with and without Parkinson’s, as well as between Parkinson’s patients with and without cognitive impairment.

They collected blood samples from 224 adults with Parkinson’s and 49 age- and sex-matched unaffected individuals, used as controls. Based on cognitive assessments, 103 patients showed no signs of cognitive problems, while 121 had cognitive impairment (81 with mild impairment and 40 classified as having dementia).

Alongside EVs filled with alpha-synuclein, researchers measured the blood levels of EVs containing beta-amyloid and phosphorylated tau proteins — whose toxic accumulation is mainly associated with Alzheimer’s, the leading cause of dementia, but also found in Parkinson’s patients.

EVs filled with the insulin-signaling protein IRS-1 were also examined, because Parkinson’s has been associated with insulin resistance — an abnormal response to the hormone insulin, causing blood sugar levels to rise.

Results showed that Parkinson’s patients had significantly fewer EVs with alpha-synuclein and IRS-1,  but more vesicles containing phosphorylated tau than healthy adults.

The progressive clumping of alpha-synuclein in neurons could lead to a lesser release of EVs containing the protein into the bloodstream, the team noted.

Parkinson’s patients with cognitive impairment also had significantly fewer EVs containing alpha-synuclein and IRS-1 relative to both patients without cognitive problems and controls.

Phosphorylated tau-filled EVs were at significantly higher levels among patients with cognitive impairment than healthy controls, but showed only a similar trend when compared with patients without cognitive problems.

Of note, the levels of EVs with phosphorylated tau were comparable between controls and cognitively normal Parkinson’s patients.

Proteins tied to Parkinson’s and Alzheimer’s ‘jointly involved’ in cognitive change

A significantly lower alpha-synuclein to pTau181 ratio was seen in Parkinson’s patients than in controls, and among patients with cognitive impairment relative to those without such problems.

“This ratio is a metric that merits further exploration in Parkinson’s disease, with the potential for biomarker use similar to the protein ratio of [beta-amyloid/phosphorylated tau] in Alzheimer’s disease,” the researchers wrote.

The amount of EVs containing the beta-amyloid protein did not differ among any of the groups.

“These novel findings support the view that aggregating proteins typically associated with Parkinson’s disease ([alpha-synuclein]) and Alzheimer’s disease ([phosphorylated tau]) are jointly involved in the [development] of cognitive impairment in Parkinson’s disease,” the team wrote.

“Further, diminished insulin signaling propagation reflected in lower [IRS-1] availability seems to characterize cognitive impairment in Parkinson’s disease and may broadly contribute to disease progression and severity,” the researchers added.

Elevated levels of alpha-synuclein-containing EVs were significantly associated with shorter disease duration in Parkinson’s patients. Fewer EVs with alpha-synuclein and IRS-1 also linked to more severe motor disease as measured by MDS-UPDRS part 3, as did higher levels of EVs carrying phosphorylated tau.

No EV biomarkers were linked to the daily levodopa equivalent dose, the combined total of Parkinson’s medications.

Further experiments demonstrated that levels of neuron-released EVs containing alpha-synuclein were better at discriminating between cognitively impaired Parkinson’s patients and healthy controls than alpha-synuclein levels in the blood alone.

Calculations confirmed that the levels of EV biomarkers including alpha-synuclein, phosphorylated tau, and IRS-1 were able to accurately distinguish between people with and without Parkinson’s, as well as between Parkinson’s patients with and without cognitive impairment.

“Our results hint at a potential synergistic relationship between [phosphorylated tau] and [alpha-synuclein] in producing cognitive impairment in Parkinson’s disease, which warrants further inquiry,” the researchers wrote.

Synergy refers to an interaction between two factors that results in a combined effect that’s greater than the sum of their separate effects.

Future studies analyzing changes over time in neuron-derived EV biomarkers from patients who moved from cognitively normal to cognitively impaired “are needed to establish the relative timeline of biomarker changes in Parkinson’s disease,” the team added.

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