Cerebrospinal fluid amyloid β and tau in LRRK2 mutation carriers

1. Published online before print December 14, 2011, doi:10.1212/WNL.0b013e31823ed101Neurology January 3, 2012vol. 78 no. 1 55-61

1. J.O. Aasly, MD, PhD*, 
2. M. Shi, PhD*, 
3. V. Sossi, PhD, 
4. T. Stewart, PhD, 
5. K.K. Johansen, MD,
6. Z.K. Wszolek, MD, 
7. R.J. Uitti, MD, 
8. K. Hasegawa, MD, PhD, 
9. T. Yokoyama, MD, PhD,
10. C.P. Zabetian, MD, 
11. H.M. Kim, MD, 
12. J.B. Leverenz, MD, 
13. C. Ginghina, MD, 
14. J. Armaly, BS,
15. K.L. Edwards, PhD, 
16. K.W. Snapinn, MS, 
17. A.J. Stoessl, MD, FRCPC and 
18. J. Zhang, MD, PhD

1. From the Department of Neurology (J.O.A., K.K.J.), St Olav's University Hospital, Trondheim; Department of Neuroscience (J.O.A., K.K.J.), Norwegian University of Science and Technology, Trondheim, Norway; Departments of Pathology (M.S., T.S., C.G., J.A., J.Z.), Neurology (C.P.Z., H.M.K., J.B.L.), and Psychiatry and Behavioral Sciences (J.B.L.), University of Washington School of Medicine, Seattle; Department of Physics & Astronomy (V.S.), University of British Columbia, Vancouver Hospital and Health Sciences Centre, Purdy Pavilion, Vancouver, Canada; Department of Neurology (Z.K.W., R.J.U.), Mayo Clinic Florida, Jacksonville; Department of Neurology (K.H., T.Y.), National Hospital Organization, Sagamihara National Hospital, Kanagawa, Japan; Geriatric Research, Education, and Clinical Center (C.P.Z.), Parkinson's Disease Research, Education, and Clinical Center (C.P.Z., H.M.K., J.B.L.), and Mental Illness Research, Education, and Clinical Center (J.B.L.), Veterans Affairs Puget Sound Health Care System, Seattle, WA; Department of Epidemiology (K.L.E., K.W.S.), University of Washington School of Public Health, Seattle; and Pacific Parkinson's Research Centre (A.J.S.), University of British Columbia & Vancouver Coastal Health, 

Objective: The goal of the current investigation was to examine a cohort of symptomatic and asymptomatic LRRK2 mutation carriers, in order to address whether the reported alterations in amyloid β (Aβ) and tau species in the CSF of patients with sporadic Parkinson disease (PD) are a part of PD pathogenesis, the aging process, or a comorbid disease in patients with PD, and to explore the possibility of Aβ and tau as markers of early or presymptomatic PD.

Methods: CSF Aβ42, total tau, and phosphorylated tau were measured with Luminex assays in 26 LRRK2 mutation carriers, who were either asymptomatic (n = 18) or had a phenotype resembling sporadic PD (n = 8). All patients also underwent PET scans with ¹⁸F-6-fluoro-L-dopa (FD), ¹¹C-(±)-α-dihydrotetrabenazine (DTBZ), and ¹¹C-d-threo-methylphenidate (MP) to measure dopaminergic function in the striatum. The levels of CSF markers were then compared to each PET measurement.

Results: Reduced CSF Aβ42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aβ42 and FD uptake. When cases were restricted to carriers of the G2019S mutation, the most commonLRRK2 variant in our cohort, significant correlations were also observed for tau.

Conclusions: The disposition of Aβ and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. A better understanding of their production, aggregation, and degradation, including changes in their CSF levels, may provide insights into the pathogenesis of PD and the potential utility of these proteins as biomarkers.