Objective/Rationale:
Evidence supports that the protein insulin-like growth factor-1 (IGF-1) may be involved in cognitive deficits. An earlier study found that low serum IGF-1 levels significantly correlated to poor performance on executive tasks and verbal memory tasks. Separately, the role of dopamine nigrostriatal dysfunction in Parkinson’s disease (PD)-related cognitive deficits has been confirmed imaging studies. Both IGF-1 and dopamine transporter (DAT) imaging will be studied as possible biomarkers of cognitive dysfunction in early PD. This study will assess relationships between IGF-1 levels and DAT uptake (use) and cognitive performance to determine if variations of such biomarkers affect cognitive performances.
Project Description:
This study uses samples available from participants in the Parkinson’s Progression Markers Initiative (PPMI). Serum of 400 PD patients and 200 healthy controls enrolled in the PPMI study will be analysed for IGF-1 levels. DAT imaging data from the same subjects will be analyzed. Finally, scores obtained from neuropsychological tasks (Montreal Cognitive Assessment, Hopkins Verbal learning Test, Benton Judgment of Line Orientation, semantic fluency, Letter Number Sequencing and Symbol Digit Modalities Test) will be used for the analysis.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Twenty-five percent of patients who have been newly diagnosed with PD may present some cognitive dysfunction. Cognitive function may decline over time, with many patients eventually developing dementia. However, some PD patients may exhibit early cognitive deficits that do not evolve into PD dementia or do so over an extended period. The development of cognitive impairment is a significant transition for patients and families, yet it is unpredictable. Thus, identification of one or more biomarkers able to track and predict cognitive dysfunction in PD is highly desirable. If this study confirms the association between IGF-1 levels and/or DAT uptake and cognitive perfomances in early PD and a predictive value of such biomarkers could be demonstrated by follow-up tests with the PPMI cohort, such biomarkers might be useful both as a clinical diagnostic tool and in the design of trials aimed at preserving cognition in PD.
Anticipated Outcome:
The possibility that IGF-1 is involved in cognitive functions is supported by evidence from laboratory and clinical studies, but the relation between serum IGF-1 levels and cognitive functions in PD has poorly been studied. This study aims to identify a serum-based biomarker useful to track cognitive dysfunction. Moreover, researchers know that the pathophysiology of cognitive impairment in PD is complex, involving multiple neurotransmitter systems and diffuse neurodegeneration. This study also aims to expand knowledge about pathophysiological substrates of cognitive impairment.
Final Outcome
We found that in people with PD at baseline the lowest IGF-1 quartile was a predictor of lower performances at the Semantic Fluency task along with age, education and gender. The lowest IGF-1 quartile was a predictor of lower performances at the Symbol Digit Modalities Score, along with age and gender. Finally, the lowest IGF-1 quartile was a predictor of lower performances at the HVLT Retention, together with age and gender. In summary, in early drug-naïve PD patients we found that lower serum IGF-1 levels predicted lower performances at baseline on cognitive tasks assessing executive function, attention and verbal memory.
This is the first large study to indicate a relationship between IGF-1 and specific cognitive domains in early PD patients. If these results are confirmed by further studies, we suggest that IGF-1 could be useful both as a biomarker of cognitive impairment and in the design of trials aimed at preserving cognition in PD.
March 2015