Microvascular changes in Parkinson´s Disease: Correlations to levodopa induced dyskinesia and grip froce control
Final Report Abstract
Levodopa induced dyskinesia (LID) is a common and potentially debilitating side-effect of chronic levodopa (LD) treatment in Parkinson’s disease (PD). There is mounting evidence that chronic dopaminergic treatment has opposing effects on cerebral blood flow (CBF) and cerebral metabolic rate (CMR). Specifically, LD treatment causes a decrease of CMR, while CBF is typically increased. The latter phenomenon is pronounced in patients with LID. It has been suggested that this decoupling of hemodynamic and metabolic responses might be attributable to microvascular brain changes. Notably, dyskinetic patients also tend to exhibit exaggerated grip force (GF) during object manipulation, and this overshoot has been associated with LD treatment. However, there is ongoing controversy whether deterioration of GF scaling is unique to LID patients (LID(+)), requires prior LD treatment, or is a feature of PD per se. To better understand the neurovascular substrate of LID and its association to clinical motor disability is crucial to facilitate the development of specific treatments for this troubling complication of chronic LD treatment. Here, we employed dual tracer PET imaging to explore if flow-metabolism dissociation was a consistent feature of chronic LD treatment or exclusively linked to LID. Further, we sought to determine if GF scaling was altered in PD patients, affected by LD treatment and differed between LID and non-LID patients (LID(-)). Lastly, we investigated whether altered GF control was linked to concurrent functional brain changes. We observed significant LD induced flow-metabolism dissociation (FMD) of the Parkinson’s disease motor-related network (PDRP), a functional brain network specifically linked to PD. Further analysis revealed that this effect was mainly driven by an increased hemodynamic response in LID(+). This group showed a significant CBF increase following LD treatment, and the hemodynamic response was relatively larger compared to LID(-). We found that in the globus pallidus/putamen, a major node of the PDRP, LID(+) patients exhibited a larger increase in CBF compared to LID(-). Hypercapnia studies revealed that LID(+) had an increased capillary reserve at this site compared to normal controls and LID(-). PD patients off medication exhibited increased GF during a grasp and lift task compared to normal controls. Subgroup analysis revealed that this difference was driven mainly by LID(+). LD treatment slightly increased GF in both LID(+) and LID(-). Moreover, we observed a positive correlation of GF levels with the magnitude of the PDRP dissociation index ((CBFON-CBFOFF)-(CMRON-CMROFF)). In summary, the data suggest that FMD is a consistent feature of chronic LD treatment and mainly driven by an abnormal hemodynamic response to LD. This phenomenon is pronounced in LID(+). The increased capillary reserve observed in the latter group suggests that enhanced angiogenesis might contribute to FMD and play a role in LID pathogenesis. Although PD patients generally exhibited exaggerated GF, it was marked in LID(+). Further, the significant correlation of FMD with GF control suggests a link of LD induced hemodynamic and metabolic brain changes with disturbed grip force control. The findings from this study have significantly substantiated our understanding of the neurovascular mechanisms underlying LID and associated deterioration of fine motor control in dyskinetic patients. Future studies exploring the microvascular integrity in the PD brain (e.g. blood brain barrier integrity) are warranted to gain more information on the causes of abnormal vasomotor response to LD treatment. The results of this work are a first step to develop targeted therapies of LID in PD patients.
Publications
- Functional brain networks in movement disorders: recent advances. Curr Opin Neurol. 2012;25(4):392-401
Holtbernd F, Eidelberg D
- Parkinson's Disease Metabolic Network Predicts Phenoconversion in Patients with Idiopathic REM Sleep Behavior Disorder Neurology February 12, 2013; 80(Meeting Abstracts 1): S19.004
Holtbernd F, Gagnon JF, Tang CC, Postuma R, Ma Y, Vendette M, Soucy JP, Eidelberg D, Montplaisir J
- Abnormal metabolic network activity in REM sleep behavior disorder. Neurology. 2014;82(7):620-7
Holtbernd F, Gagnon JF, Postuma RB, Ma Y, Tang CC, Feigin A, Dhawan V, Vendette M, Soucy JP, Eidelberg D, Montplaisir J
(See online at https://doi.org/10.1212/WNL.0000000000000130) - The role of neuroimaging in the differential diagnosis of parkinsonian syndromes. Semin Neurol. 2014 Apr;34(2):202-9. Epub 2014 Jun 25
Holtbernd F, Eidelberg D
(See online at https://doi.org/10.1055/s-0034-1381733) - Deficits in tongue motor control are linked to microstructural brain damage in Multiple Sclerosis : a pilot study. BMC Neurology 2015, 15:190 (6 S.)
Holtbernd F, Deppe M, Bachmann R, Mohammadi S, Ringelstein EB, Reilmann R
(See online at https://doi.org/10.1186/s12883-015-0451-9) - Dopaminergic correlates of metabolic network activity in Parkinson’s disease. Human Brain Mapping, Vol 36 Issue 9, September 2015, Pages 3575-3585
Holtbernd F, Ma Y, Peng S, Schwartz F, Timmermann L, Kracht L, Fink GR, Tang CC, Eidelberg D, Eggers C
(See online at https://doi.org/10.1002/hbm.22863) - Longitudinal changes in the motor learning-related brain activation response in presymptomatic Huntington’s disease. PLoS ONE 11(5): e0154742, 2016
Holtbernd F, Tang CC, Feigin A, Dhawan V, Ghilardi MF, Paulsen JD, Guttman M, Eidelberg D
(See online at https://doi.org/10.1371/journal.pone.0154742)
