Search

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.

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

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.