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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.

BACKGROUND: Parkinson's disease (PD) is the second‐most common neurodegenerative disorder after Alzheimer's disease; however, to date, there is no approved treatment that stops or slows down disease progression. Over the past decades, neuroimaging studies, including molecular imaging and MRI are trying to provide insights into the mechanisms underlying PD. METHODS: This work utilized a literature review. RESULTS: It is now becoming clear that these imaging modalities can provide biomarkers that can objectively detect brain changes related to PD and monitor these changes as the disease progresses, and these biomarkers are required to establish a breakthrough in neuroprotective or disease‐modifying therapeutics. CONCLUSIONS: Here, we provide a review of recent observations deriving from PET, single‐positron emission tomography, and MRI studies exploring PD and other parkinsonian disorders.

Rationale and Objectives Parkinson disease (PD) is a progressive neurodegenerative disorder affecting motor and cognitive functions. Prior studies showed that patients with PD and diabetes (DM) demonstrate worse clinical outcomes compared to nondiabetic subjects with PD. Our study aimed at defining the relationship between DM, gray matter volume, and cognition in patients with PD. Materials and Methods This study included 36 subjects with PD (12 with DM, 24 without DM, mean age = 66). Subjects underwent high-resolution T1-weighted brain magnetic resonance imaging, [11C]dihydrotetrabenazine positron emission tomography imaging to quantify nigrostriatal dopaminergic denervation, clinical, and cognitive assessments. Magnetic resonance images were postprocessed to determine total and lobar cortical gray matter volumes. Cognitive testing scores were converted to z-scores for specific cognitive domains and a composite global cognitive z-score based on normative data computed. Analysis of covariance, accounting for effects of age, gender, intracranial volume, and striatal [11C]dihydrotetrabenazine binding, was used to test the relationship between DM and gray matter volumes. Results Impact of DM on total gray matter volume was significant (P = 0.02). Post hoc analyses of lobar cortical gray matter volumes revealed that DM was more selectively associated with lower gray matter volumes in the frontal regions (P = 0.01). Cognitive post hoc analyses showed that interaction of total gray matter volume and DM status was significantly associated with composite (P = 0.007), executive (P = 0.02), and visuospatial domain cognitive z-scores (P = 0.005). These associations were also significant for the frontal cortical gray matter. Conclusion DM may exacerbate brain atrophy and cognitive functions in PD with greater vulnerability in the frontal lobes. Given the high prevalence of DM in the elderly, delineating its effects on patient outcomes in the PD population is of importance.

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.

Highlights • Basal ganglia connectivity and its role in gait is not well understood. • Basal ganglia connectivity grouped into high and low connectivity. • Groups were not spatially distinct within the basal ganglia. • Lower connectivity was associated with slower gait speed. • Association was significant after adjusting for other locomotor risk factors., Background and Aim The basal ganglia are critical for planned locomotion, but their role in age-related gait slowing is not well known. Spontaneous regional co-activation of brain activity at rest, known as resting state connectivity, is emerging as a biomarker of functional neural specialization of varying human processes, including gait. We hypothesized that greater connectivity amongst regions of the basal ganglia would be associated with faster gait speed in the elderly. We further investigated whether this association was similar in strength to that of other risk factors for gait slowing, specifically white matter hyperintensities (WMH). Methods A cohort of 269 adults (79–90 years, 146 females, 164 White) were assessed for gait speed (m/sec) via stopwatch; brain activation during resting state functional magnetic resonance imaging, WMH, and gray matter volume (GMV) normalized by intracranial volume via 3T neuroimaging; and risk factors of poorer locomotion via clinical exams (body mass index (BMI), muscle strength, vision, musculoskeletal pain, cardiometabolic conditions, depressive symptoms, and cognitive function). To understand whether basal ganglia connectivity shows distinct clusters of connectivity, we conducted a k-means clustering analysis of regional co-activation among the substantia nigra, nucleus accumbens, subthalamic nucleus, putamen, pallidum, and caudate. We conducted two multivariable linear regression models: (1) with gait speed as the dependent variable and connectivity, demographics, WMH, GMV, and locomotor risk factors as independent variables and (2) with basal ganglia connectivity as the dependent variable and demographics, WMH, GMV, and locomotor risk factors as independent variables. Results We identified two clusters of basal ganglia connectivity: high and low without a distinct spatial distribution allowing us to compute an average connectivity index of the entire basal ganglia regional connectivity (representing a continuous measure). Lower connectivity was associated with slower gait, independent of other locomotor risk factors, including WMH; the coefficient of this association was similar to those of other locomotor risk factors. Lower connectivity was significantly associated with lower BMI and greater WMH. Conclusions Lower resting state basal ganglia connectivity is associated with slower gait speed. Its contribution appears comparable to WMH and other locomotor risk factors. Future studies should assess whether promoting higher basal ganglia connectivity in older adults may reduce age-related gait slowing.

Older age and cerebral small vessel disease (cSVD) predict slower gait. However, some adults maintain faster gait speed despite older age and/or the presence of cSVD. We hypothesize that higher levels of nigrostriatal dopamine can help offset the detrimental effects of older age and cSVD on gait speed. Cross-sectional data are from 85 adults aged 20–85, 56% females without Parkinson’s disease or other neurological diseases. cSVD was quantified as white matter hyperintensities rated on a 0–9 scale. Nigrostriatal DA levels were quantified via molecular imaging of the DA transporter (DAT) ligand. The inverse correlations of age and cSVD with gait speed were stronger for those with DATmedian (rho (p value): -0.18 (0.3) and -0.33 (0.05)). Maintaining higher nigrostriatal DA levels late in life may promote resilience against gait slowing due to older and/or cSVD.

Objective: To investigate the relationship between age-associated MRI leukoaraiosis or white matter hyperintensities (WMH) and cortical acetylcholinesterase (AChE) activity. Background: One possible mechanism of cognitive decline in elderly individuals with leukoaraiosis is disruption of cholinergic fibers by strategically located white matter lesions. Periventricular lesions may have a higher chance of disrupting cholinergic projections compared with more superficial nonperiventricular white matter lesions because of anatomic proximity to the major cholinergic axonal projection bundles that originate from the basal forebrain. Methods: Community-dwelling, middle-aged and elderly subjects without dementia (mean age 71.0 9.2 years; 55– 84 years; n 18) underwent brain MRI and AChE PET imaging. The severity of periventricular and nonperiventricular WMH on fluid-attenuated inversion recovery MRI images was scored using the semiquantitative rating scale of Scheltens et al. [ 11 C]methyl-4piperidinyl propionate AChE PET imaging was used to assess cortical AChE activity. Agecorrected Spearman partial rank correlation coefficients were calculated. Results: The severity of periventricular (R 0.52, p 0.04) but not nonperiventricular (R 0.20, not significant) WMH was inversely related to global cortical AChE activity. Regional cortical cholinergic effects of periventricular WMH were most significant for the occipital lobe (R 0.58, p 0.02). Conclusions: The presence of periventricular but not nonperiventricular white matter hyperintensities (WMH) is significantly associated with lower cortical cholinergic activity. These findings support a regionally specific disruption of cholinergic projection fibers by WMH. Neurology ® 2009;72:1411–1416

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...

Variants in genes regulating dopamine transmission affect performance on tasks including working memory and executive function as well as temporal processing and sequence learning. In the current study, we determined whether a dopamine D2 receptor DNA sequence polymorphism interacts with L-DOPA during motor tasks in patients with Parkinson's disease (PD). Forty-five PD patients were genotyped for the DRD2 polymorphism (rs 1076560, G > T). Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF L-DOPA states. For motor sequence learning, DRD2 genotype mediated L-DOPA effects such that L-DOPA associated improvements were only observed in the minor T allele carriers (associated with lower D2 receptor availability, t10 = −2.71, p = 0.022), whereas G homozygotes showed no performance change with L-DOPA. For the grooved pegboard test, performance improved with L-DOPA independent of patients’ DRD2 genotype. Collectively these results demonstrate that common DRD2 allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals.