Study Rationale:
Vitamin B12 levels are lower in people with Parkinson’s disease. Our prior investigation showed that lower B12 levels were associated with more rapid worsening of gait and stability. Low B12 may be linked to more rapid progression because this vitamin supports myelination, when a substance called myelin, made up of fatty lipids and proteins, accumulates around nerve cells. Myelin helps nerve cells transmit information faster. Another theory is that B12 impacts LRRK2. A recent study shows that LRRK2 protein activity is modulated by B12 levels. Mutations in the LRRK2 gene can cause Parkinson’s and some people with Parkinson’s, even without the mutation, have higher LRRK2 levels. It is possible that low B12 levels could affect Parkinson’s progression through its effect on LRRK2.
Hypothesis:
We hypothesize that low vitamin B12 levels increase the rate of progression of Parkinson’s. If this finding is validated, the effect could happen by effects of B12 on nervous system myelination or by allowing increased activity of LRRK2.
Study Design:
We will measure B12 and two other components associated with B12 deficiency from blood samples collected in three recent clinical trials. SURE-PD2 and SURE-PD3 were trials measuring impact of the compound inosine to raise levels of the antioxidant urate and slow Parkinson’s progression. STEADY-PD3 evaluated the calcium channel blocker isradipine for its impact on Parkinson’s progression. Both SURE-PD3 and STEADY-PD3 found no significant impact on Parkinson’s progression, but are providing valuable samples for study such as this one.
This B12 study will use samples collected from participants at the start of the study (baseline) and study completion and determine whether levels of B12 (or of the other B12 components) are associated with Parkinson’s progression. We will also examine whether vitamin use or initiation of dopamine medications is associated with the baseline values and/or changes in B12 levels over time. Finally, using a biomarker of LRRK2 activity, we will determine whether greater LRRK2 activity is associated with lower B12 levels in blood.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
If we find that low B12 levels are associated with more rapid progression of Parkinson’s, this may motivate clinicians to consider measurement of B12 levels at the time of diagnosis and to consider recommending B12 supplementation.
Next Steps for Development:
If we find that low B12 levels are associated with more rapid progression of Parkinson’s, then this would provide compelling evidence to directly test whether B12 supplementation is associated with slower disease progression. Moreover, if low B12 levels are associated with increased LRRK2 levels, then this will provide further support for LRRK2 inhibitor medications to be used in people with Parkinson’s without a LRRK2 mutation. (These medications are in testing in people with Parkinson’s with and without mutations.)