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Objective To examine whether the association between dopamine-related genotype and gait speed differs according to frailty status or race. Design Cross-sectional population-based study (Cardiovascular Health Study). Setting Multicenter study, four U.S. sites. Participants Volunteer community-dwelling adults aged 65 years and older, without evidence of Parkinson's disease (N = 3,744; 71 years; 82% White; 39% male). Measurements Gait speed (usual pace; m/s), physical frailty (Fried definition), and genetic polymorphism of catechol-O-methyltransferase (COMT; rs4680), an enzyme regulating tonic brain dopamine levels, were assessed. Interaction of COMT by frailty and by race predicting gait speed were tested, and, if significant, analyses were stratified. Multivariable regression models of COMT predicting gait speed were adjusted for demographics and locomotor risk factors. Sensitivity analyses were repeated, stratified by clinical cutoffs of gait speed (0.6 and 1.0 m/s) instead of frailty status. Results The interaction of COMT by frailty and COMT by race were P = .02 and P = .01, respectively. Compared with Met/Met (higher dopaminergic signaling), the Val/Val group (lower dopaminergic signaling) walked marginally more slowly in the full cohort (0.87 vs 0.89 m/s; P = .2). Gait speed differences were significant for frail (n = 220; 0.55 vs 0.63 m/s; P = .03), but not for prefrail (n = 1,691; 0.81 vs 0.81 m/s; P = .9) or nonfrail (n = 1,833; 0.98 vs 0.97 m/s; P = .7); results were similar in fully adjusted models. Among frail, associations were similar for Whites and Blacks, with statistical significance for Whites only. Associations stratified by clinical cutoffs of gait speed were not significant. Conclusion The association of dopamine-related genotype with gait speed is stronger among adults with frailty compared with those without frailty. The potential effects of dopaminergic signaling on preserving physical function in biracial cohorts of frail adults should be further examined.

Purpose This joint practice guideline or procedure standard was developed collaboratively by the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). The goal of this guideline is to assist nuclear medicine practitioners in recommending, performing, interpreting, and reporting the results of dopaminergic imaging in parkinsonian syndromes. Methods Currently nuclear medicine investigations can assess both presynaptic and postsynaptic function of dopaminergic synapses. To date both EANM and SNMMI have published procedural guidelines for dopamine transporter imaging with single photon emission computed tomography (SPECT) (in 2009 and 2011, respectively). An EANM guideline for D2 SPECT imaging is also available (2009). Since the publication of these previous guidelines, new lines of evidence have been made available on semiquantification, harmonization, comparison with normal datasets, and longitudinal analyses of dopamine transporter imaging with SPECT. Similarly, details on acquisition protocols and simplified quantification methods are now available for dopamine transporter imaging with PET, including recently developed fluorinated tracers. Finally, [18F]fluorodopa PET is now used in some centers for the differential diagnosis of parkinsonism, although procedural guidelines aiming to define standard procedures for [18F]fluorodopa imaging in this setting are still lacking. Conclusion All these emerging issues are addressed in the present procedural guidelines for dopaminergic imaging in parkinsonian syndromes.

Anticholinergic medications (A-chol) increase risk for falls; higher dopaminergic signaling may provide resilience to these effects. In 2489 older adults (mean age=74; 52% women) with 10 years of data on medication use, falls, and dopaminergic genotype (catechol-O-methyltransferase (COMT)), we assessed the association of A-chol use with recurrent falls (≥2) over the subsequent 12 months using generalized estimating equations. Effect modification by COMT (met/met, higher dopamine signaling, n=473 vs val carriers, lower dopamine signaling, n=2016) was tested; analyses were then stratified by COMT and adjusted for demographics and A-chol use indicators. During follow-up, 843 people reported recurrent falls. A-chol use doubled the odds of recurrent falls (OR [95%CI]=2.13[1.74, 2.60]), with a suggested effect modification by COMT (p=0.1). The association was present in val carriers (adjusted OR [95%CI]=1.93[1.36, 2.73]) but not in met/met (adjusted OR [95%CI]=1.30[0.53, 3.22]). Higher dopaminergic signaling may provide protection against the effects of A-chol use on fall risk.

Objective: To examine whether the association between dopamine-related genotype and gait speed differs according to frailty status or race. Design: Cross-sectional population-based study (Cardiovascular Health Study) Setting: Multi-center study, 4 US sites. Participants: Volunteer community-dwelling adults aged 65 and older, without evidence of Parkinson’s Disease (N= 3,744, 71 years, 82% white, 39% male). Measurements: Gait speed (usual pace, m/sec), physical frailty (Fried definition), and genetic polymorphism of Catechol-O-methyltransferase (COMT, rs4680), an enzyme regulating tonic brain dopamine levels, were assessed. Interaction of COMT by frailty and by race predicting gait speed were tested, and, if significant, analyses were stratified. Multivariable regression models of COMT predicting gait speed were adjusted for demographics and locomotor risk factors. Sensitivity analyses were repeated stratified by clinical cut-offs of gait speed (0.6 and 1.0m/sec) instead of frailty status. Results: Compared to Met/Met (higher dopaminergic signaling), the Val/Val group (lower dopaminergic signaling) walked marginally more slowly in the full cohort (0.87 vs 0.89 m/sec, p=0.2). The interaction of COMT by frailty and COMT by race predicting gait speed were p=0.02 and p=0.01, respectively. Gait speed differences by genotype were significant for frail (n=220, 0.55 vs 0.63 m/sec, p=0.03), but not for pre-frail (n=1691, 0.81 vs 0.81 m/sec, p=0.9), or non-frail (n=1833, 0.98 vs 0.97 m/sec, p=0.7); results were similar in fully adjusted models. Among frail, associations were similar for whites and blacks, but statistically significant for whites only. Associations stratified by clinical cut-offs of gait speed were not significant. Conclusion: The association of dopamine-related genotype with gait speed is stronger among adults with frailty compared to those without. The potential effects of dopaminergic signaling on preserving physical function in frail adults should be further examined. This is significant to public health as it could improve quality of life of older adults and decrease adverse health outcomes.

We assessed associations of slow gait with measures of dopaminergic (catechol-O-methyltransferase (COMT) genotype, indicator of synaptic dopamine levels) and vascular (white matter hyperintensities (WMH), dichotomized at the median) factors in a cohort of older adults (n=215; age= 82.6 (SD=2.6); 58.0% female; 38.8% black; 35 Met/Met COMT Val158Met (higher dopamine) genotype). Mean gait speed was 0.92 m/s. There was a significant interaction (p=0.048) between WMH and COMT. Stratified analyses reveled a strong association between WMH and gait speed among COMT Val carriers (beta=-9.9, CI: -16.5, -3.3; lower dopamine), but not for Met/Met (beta=5.3, CI: -14.4, 24.9; higher dopamine) independent of covariates. Differences persisted over four years of follow-up. Higher synaptic dopamine, as indicated by COMT genotype, may have a protective effect on gait speed in the presence of WMH. The dopaminergic system may be an intervention target for increasing brain resilience and enhancing functional outcomes in older adults.

Individuals learn new skills at different rates. Given the involvement of corticostriatal pathways in some types of learning, variations in dopaminergic transmission may contribute to these individual differences. Genetic polymorphisms of the catechol- O-methyltransferase (COMT) enzyme and dopamine receptor D2 (DRD2) genes partially determine cortical and striatal dopamine availability, respectively. Individuals who are homozygous for the COMT methionine ( met) allele show reduced cortical COMT enzymatic activity, resulting in increased dopamine levels in the prefrontal cortex as opposed to individuals who are carriers of the valine ( val) allele. DRD2 G-allele homozygotes benefit from a higher striatal dopamine level compared with T-allele carriers. We hypothesized that individuals who are homozygous for COMT met and DRD2 G alleles would show higher rates of motor learning. Seventy-two young healthy females (20 ± 1.9 yr) performed a sensorimotor adaptation task and a motor sequence learning task. A nonparametric mixed model ANOVA revealed that the COMT val-val group demonstrated poorer performance in the sequence learning task compared with the met-met group and showed a learning deficit in the visuomotor adaptation task compared with both met-met and val-met groups. The DRD2 TT group showed poorer performance in the sequence learning task compared with the GT group, but there was no difference between DRD2 genotype groups in adaptation rate. Although these results did not entirely come out as one might predict based on the known contribution of corticostriatal pathways to motor sequence learning, they support the role of genetic polymorphisms of COMT val158met (rs4680) and DRD2 G>T (rs 1076560) in explaining individual differences in motor performance and motor learning, dependent on task type.

Mild to moderate Parkinson's disease shows more denervation in the posterodorsal striatum and sparing of the anteroventral striatum. Dopaminergic medications can interfere with anteroventral striatum function by overdosing this relatively intact structure. The authors determined how regional striatal denervation affects medication-associated sequence learning impairment in Parkinson's disease. Eighteen Parkinson's patients performed motor sequence learning on and off levodopa. Patients underwent 11C-dihydrotetrabenazine positron emission tomography scans to measure nigrostriatal denervation. Patients with more preserved putamen were more likely to exhibit levodopa-associated sequence learning impairments. Furthermore, the ratio of denervation in the anterior to posterior dorsal putamen predicted the level of learning differences on and off levodopa. These results demonstrate that the spatial pattern of nigrostriatal dopaminergic denervation predicts medication responsiveness for motor sequence lea...