Prevalence of Late-Stage Parkinson's Disease in the US Healthcare System: Insights from TriNetX.

BACKGROUND: Patients in late-stage Parkinson's disease (PDLS) are caregiver-dependent, have low quality of life, and higher healthcare costs. OBJECTIVE: To estimate the prevalence of PDLS patients in the current US healthcare system. METHODS: We downloaded the 2010-2022 data from the TriNetX Diamond claims network that consists of 92 US healthcare sites. PD was identified using standard diagnosis codes, and PDLS was identified by the usage of wheelchair dependence, personal care assistance, and/or presence of diagnoses of dementia. Age of PDLS identification and survival information were obtained and stratified by demographic and the disability subgroups. RESULTS: We identified 1,031,377 PD patients in the TriNetX database. Of these, 18.8% fitted our definition of PDLS (n = 194,297), and 10.2% met two or more late-stage criteria. Among all PDLS, the mean age of PDLS identification was 78.1 (±7.7) years, and 49% were already reported as deceased. PDLS patients were predominantly male (58.5%) with similar distribution across PDLS subgroups. The majority did not have race (71%) or ethnicity (69%) information, but for the available information >90% (n = 53,162) were White, 8.2% (n = 5121) Hispanic/Latino, 7.8% (n = 4557) Black, and <0.01% (n = 408) Asian. Of the PDLS cohort, 71.6% identified with dementia, 12.9% had personal care assistance, and 4.8% were wheelchair-bound. CONCLUSIONS: Late-stage patients are a significant part of the PD landscape in the current US healthcare system, and largely missed by traditional motor-based disability staging. It is imperative to include this population as a clinical, social, and research priority. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Susceptibility Magnetic Resonance Imaging Correlates with Glial Density and Tau in the Substantia Nigra Pars Compacta.

BACKGROUND: Susceptibility magnetic resonance imaging (MRI) is sensitive to iron-related changes in the substantia nigra pars compacta (SNc), the key pathologic locus of parkinsonisms. It is unclear, however, if iron deposition in the SNc is associated with its neurodegeneration. OBJECTIVE: The objective of this study was to test whether susceptibility MRI metrics in parkinsonisms are associated with SNc neuropathologic features of dopaminergic neuron loss, gliosis, and α-synuclein and tau burden. METHODS: This retrospective study included 27 subjects with both in vivo MRI and postmortem data. Multigradient echo imaging was used to derive the apparent transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM) in the SNc. Archived midbrain slides that were stained with hematoxylin and eosin, anti-α-synuclein, and anti-tau were digitized to quantify neuromelanin-positive neuron density, glial density, and the percentages of area occupied by positive α-synuclein and tau staining. MRI-histology associations were examined using Pearson correlations and regression. RESULTS: Twenty-four subjects had postmortem parkinsonism diagnoses (Lewy body disorder, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration), two had only Alzheimer's neuropathology, and one exhibited only mild atrophy. Among all subjects, both R2* and QSM were associated with glial density (r ≥ 0.67; P < 0.001) and log-transformed tau burden (r ≥ 0.53; P ≤ 0.007). Multiple linear regression identified glial density and log-transformed tau as determinants for both MRI metrics (R2 ≥ 0.580; P < 0.0001). Neither MRI metric was associated with neuron density or α-synuclein burden. CONCLUSIONS: R2* and QSM are associated with both glial density and tau burden, key neuropathologic features in the parkinsonism SNc. © 2023 International Parkinson and Movement Disorder Society.

A Dopamine D1 Agonist Versus Methylphenidate in Modulating Prefrontal Cortical Working Memory.

Methylphenidate is used widely to treat symptoms of attention-deficit/hyperactivity disorder (ADHD), but like other stimulants has significant side effects. This study used a rodent model (spontaneously hypertensive rat) of spatial working memory (sWM) to compare the effects of methylphenidate with the novel dopamine D1-like receptor agonist 2-methyldihydrexidine. Acute oral administration of methylphenidate (1.5 mg/kg) caused sWM improvement in half of the tested rats, but impairment in the others. Both improvement or impairment were eliminated by administration of the D1 antagonist SCH39266 directly into the prefrontal cortex (PFC). Conversely, 2-methyldihydrexidine showed greater sWM improvement compared with methylphenidate without significant impairment in any subject. Its effects correlated negatively with vehicle-treated baseline performance (i.e., rats with lower baseline performance improved more than rats with higher baseline performance). These behavioral effects were associated with neural activities in the PFC. Single neuron firing rate was changed, leading to the alteration in neuronal preference to correct or error behavioral responses. Overall, 2-methyldihydrexidine was superior to methylphenidate in decreasing the neuronal preference, prospectively, in the animals whose behavior was improved. In contrast, methylphenidate, but not 2-methyldihydrexidine, significantly decreased neuronal preference, retrospectively, in those animals who had impaired performance. These results suggest that a D1 agonist may be more effective than methylphenidate in regulating sWM-related behavior through neural modulation of the PFC, and thus may be superior to methylphenidate or other stimulants as ADHD pharmacotherapy. SIGNIFICANCE STATEMENT: Methylphenidate is effective in ADHD by its indirect agonist stimulation of dopamine and/or adrenergic receptors, but the precise effects on specific targets are unclear. This study compared methylphenidate to a dopamine D1 receptor-selective agonist by investigating effects on working memory occurring via neural modulation in the prefrontal cortex. The data suggest that pharmacological treatment selectively targeting the dopamine D1 may offer a superior approach to ADHD pharmacotherapy.

Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage.

BACKGROUND: Higher nigral iron has been reported in Parkinson's disease (PD). OBJECTIVE: The aim is to understand the dynamics of nigral iron accumulation in PD and its association with drug treatment. METHODS: Susceptibility magnetic resonance imaging data were obtained from 79 controls and 18 drug-naive (PDDN ) and 87 drug-treated (PDDT ) PD patients. Regional brain iron in basal ganglia and cerebellar structures was estimated using quantitative susceptibility mapping. Nigral iron was compared between PDDN and PDDT subgroups defined by disease duration (early [PDE, <2 years], middle [PDM, 2-6 years], and later [PDL, >6 years]). Associations with both disease duration and types of antiparkinson drugs were explored using regression analysis. RESULTS: Compared to controls, PDDN had lower iron in the substantia nigra (P = 0.018), caudate nucleus (P = 0.038), and globus pallidus (P = 0.01) but not in the putamen or red nucleus. In contrast, PDDT had higher iron in the nigra (P < 0.001) but not in other regions, compared to either controls or PDDN . Iron in the nigra increased with disease duration (PDE > PDDN [P = 0.001], PDM > PDE [P = 0.045]) except for PDM versus PDL (P = 0.226). Levodopa usage was associated with higher (P = 0.013) nigral iron, whereas lower nigral iron was correlated with selegiline usage (P = 0.030). CONCLUSION: Nigral iron is lower before the start of dopaminergic medication and then increases throughout the disease until it plateaus at late stages, suggesting increased iron may not be an etiological factor. Interestingly, PD medications may have differential associations with iron accumulation that need further investigation. © 2022 International Parkinson and Movement Disorder Society.

Decoupling of Global Brain Activity and Cerebrospinal Fluid Flow in Parkinson's Disease Cognitive Decline.

BACKGROUND: Deposition and spreading of misfolded proteins (α-synuclein and tau) have been linked to Parkinson's disease cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep-dependent global brain activity is coupled to CSF flow, which may reflect glymphatic function. OBJECTIVE: The objective of this current study was to determine if the decoupling of brain activity-CSF flow is linked to Parkinson's disease cognitive dysfunction. METHODS: Functional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment [MoCA]) scores were collected from 60 Parkinson's disease and 58 control subjects. Parkinson's disease patients were subgrouped into those with mild cognitive impairment (MoCA < 26), n = 31, and those without mild cognitive impairment (MoCA ≥ 26), n = 29. The coupling strength between the resting-state global blood-oxygen-level-dependent signal and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements. RESULTS: Global blood-oxygen-level-dependent signal-CSF coupling decreased significantly (P < 0.006) in Parkinson's disease patients showing mild cognitive impairment, compared with those without mild cognitive impairment and controls. Reduced global blood-oxygen-level-dependent signal-CSF coupling was associated with decreased MoCA scores present in Parkinson's disease patients (P = 0.005) but not in controls (P = 0.65). Weaker global blood-oxygen-level-dependent signal-CSF coupling in Parkinson's disease patients also was associated with a thinner right entorhinal cortex (Spearman's correlation, -0.36; P = 0.012), an early structural change often seen in Alzheimer's disease. CONCLUSIONS: The decoupling between global brain activity and associated CSF flow is related to Parkinson's disease cognitive impairment. © 2021 International Parkinson and Movement Disorder Society.

Magnetic resonance T1w/T2w ratio: A parsimonious marker for Parkinson disease.

OBJECTIVE: Newer magnetic resonance imaging (MRI) techniques have shown promise in capturing early Parkinson disease (PD)-related changes in the substantia nigra pars compacta (SNc), the key pathological loci. Their translational value, however, is hindered by technical complexity and inconsistent results. METHODS: A novel yet simple MRI contrast, the T1w/T2w ratio, was used to study 76 PD patients and 70 controls. The T1w/T2w ratio maps were analyzed using both voxel-based and region-of-interest approaches in normalized space. The sensitivity and specificity of the SNc T1w/T2w ratio in discriminating between PD and controls also were assessed. In addition, its diagnostic performance was tested in a subgroup of PD patients with disease duration ≤2 years (PDE). A second independent cohort of 73 PD patients and 49 controls was used for validation. RESULTS: Compared to controls, PD patients showed a higher T1w/T2w ratio in both the right (cluster size = 164mm3 , p < 0.0001) and left (cluster size = 213mm3 , p < 0.0001) midbrain that was located ventrolateral to the red nucleus and corresponded to the SNc. The region-of-interest approach confirmed the group difference in the SNc T1w/T2w ratio between PD and controls (p < 0.0001). The SNc T1w/T2w ratio had high sensitivity (0.908) and specificity (0.80) to separate PD and controls (area under the curve [AUC] = 0.926), even for PDE patients (AUC = 0.901, sensitivity = 0.857, specificity = 0.857). These results were validated in the second cohort. INTERPRETATION: The T1w/T2w ratio can detect PD-related changes in the SNc and may be used as a novel, parsimonious in vivo biomarker for the disease, particularly for early stage patients, with high translational value for clinical practice and research. ANN NEUROL 2019;85:96-104.

Tryptophan Metabolites Are Associated With Symptoms and Nigral Pathology in Parkinson's Disease.

BACKGROUND: The objective of this study was to determine whether neurotoxic kynurenine metabolites, induced by inflammation, in plasma and cerebrospinal fluid (CSF) are associated with symptom severity and nigral pathology in Parkinson's disease (PD). METHODS: Clinical and MRI data were obtained from 97 PD and 89 controls. We used ultra-performance liquid chromatography to quantify kynurenine metabolites and high-sensitivity multiplex assays to quantify inflammation in plasma and CSF. We evaluated group-wise differences as well as associations between the biomarkers, motor and nonmotor symptoms, and nigral R2* (MRI metric reflecting iron content). RESULTS: PD subjects had >100% higher 3-hydroxykynurenine and 14% lower 3-hydroxyanthranilic acid in plasma. The 3-HK in plasma was closely associated with both symptom severity and disease duration. PD subjects also had 23% lower kynurenic acid in the CSF. Higher CSF levels of the excitotoxin quinolinic acid were associated with more severe symptoms, whereas lower levels of the neuroprotective kynurenic acid were linked to olfactory deficits. An elevated quinolinic acid/picolinic acid ratio in the CSF correlated with higher R2* values in the substantia nigra in the entire cohort. Plasma C-reactive protein and serum amyloid alpha were associated with signs of increased kynurenine pathway activity in the CSF of PD patients, but not in controls. CONCLUSIONS: In PD, the kynurenine pathway metabolite levels are altered in both the periphery and the central nervous system, and these changes are associated with symptom severity. Replication studies are warranted in other cohorts, and these can also explore if kynurenine metabolites might be PD biomarkers and/or are involved in PD pathogenesis. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Synergic control of action in levodopa-naïve Parkinson's disease patients: II. Multi-muscle synergies stabilizing vertical posture.

Postural instability is a major disabling feature in Parkinson's disease (PD). We quantified the organization of leg and trunk muscles into synergies stabilizing the center of pressure (COP) coordinate within the uncontrolled manifold hypothesis in levodopa-naïve patients with PD and age-matched control subjects. The main hypothesis was that changes in the synergic control of posture are present early in the PD process even before levodopa exposure. Eleven levodopa-naïve patients with PD and 11 healthy controls performed whole-body cyclical voluntary sway tasks and a self-initiated load-release task during standing on a force plate. Surface electromyographic activity in 13 muscles on the right side of the body was analyzed to identify muscle groups with parallel scaling of activation levels (M-modes). Data were collected both before ("off-drug") and approximately 60 min after the first dose of 25/100 carbidopa/levodopa ("on-drug"). COP-stabilizing synergies were quantified for the load-release task. Levodopa-naïve patients with PD showed no COP-stabilizing synergy "off-drug", whereas controls showed posture-stabilizing multi-M-mode synergy. "On-drug", patients with PD demonstrated a significant increase in the synergy index. There were no significant drug effects on the M-mode composition, anticipatory postural adjustments, indices of motor equivalence, or indices of COP variability. The results suggest that levodopa-naïve patients with PD already show impaired posture-stabilizing multi-muscle synergies that may be used as promising behavioral biomarkers for emerging postural disorders in PD. Moreover, levodopa modified synergy metrics differently in these levodopa-naïve patients compared to a previous study of patients on chronic antiparkinsonian medications (Falaki et al. in J Electromyogr Kinesiol 33:20-26, 2017a), suggesting different neurocircuitry involvement.

Synergic control of action in levodopa-naïve Parkinson's disease patients: I. Multi-finger interaction and coordination.

We explored the origin of the impaired control of action stability in Parkinson's disease (PD) by testing levodopa-naïve PD patients to disambiguate effects of PD from possible effects of long-term exposure to levodopa. Thirteen levodopa-naïve PD patients and 13 controls performed single- and multi-finger force production tasks, including producing a self-paced quick force pulse into a target. A subgroup of patients (n = 10) was re-tested about 1 h after the first dose of levodopa. Compared to controls, PD patients showed lower maximal forces and synergy indices stabilizing total force (reflecting the higher inter-trial variance component affecting total force). In addition, PD patients showed a trend toward shorter anticipatory synergy adjustments (a drop in the synergy index in preparation to a quick action) and larger non-motor equivalent finger force deviations. Lower maximal force, higher unintentional force production (enslaving) and higher inter-trial variance indices occurred in PD patients after one dosage of levodopa. We conclude that impairment in synergies is present in levodopa-naïve patients, mainly in indices reflecting stability (synergy index), but not agility (anticipatory synergy adjustments). A single dose of levodopa, however, did not improve synergy indices, as it did in PD patients on chronic anti-PD medication, suggesting a different mechanism of action. The results suggest that indices of force-stabilizing synergies may be used as an early behavioral sign of PD, although it may not be sensitive to acute drug effects in drug-naïve patients.

Brain cholesterol metabolism and Parkinson's disease.

BACKGROUND: Circulating cholesterol levels have been linked to PD, but not directly to brain physiology. OBJECTIVE: To assess whether brain cholesterol metabolism is related to PD. METHODS: Sixty PD patients and 64 controls were recruited from an academic movement disorder clinic (2009-2012). Thirty-five PD patients and 33 controls returned approximately 36 months later. Fasting plasma (S)24-OH-cholesterol (brain-derived cholesterol metabolite) and 27-OH-cholesterol (peripheral cholesterol metabolite) were quantified. Odds ratios for PD were derived from logistic regression models, adjusting for potential confounders. Relationships between the oxysterols and clinical measurements were explored using Spearman correlation coefficients. RESULTS: Mean age of PD subjects was 63.8 ± 8.3 years and disease duration was 5.0 ± 5.4 years. Plasma (S)24-OH-cholesterol levels were inversely associated with the odds of having PD, with an odds ratio of 0.92 (95% confidence interval: 0.87-0.97) for each 1-ng/mL increase (P = 0.004). Compared to the lowest tertile, the odds ratio was 0.34 (0.12-0.98) for the second tertile (P = 0.045) and 0.08 (0.02-0.31) for the highest tertile (P < 0.001). Higher (S)24-OH-cholesterol levels also were correlated with better sense of smell (r = 0.35; P = 0.01). No significant associations were found between clinical measures and 27-OH-cholesterol, a peripheral cholesterol metabolite. Furthermore, (S)24-OH-cholesterol levels were stable over time, whereas 27-OH-cholesterol decreased with time in both cases and controls. CONCLUSIONS: Results indicate that plasma (S)24-OH-cholesterol (possibly reflecting brain cholesterol metabolism) is inversely linked to PD, is relatively stable over time, and may serve as a new biomarker for PD. Further investigation is necessary to determine the mechanistic and clinical implications. © 2019 International Parkinson and Movement Disorder Society.

Individual preferences in motor coordination seen across the two hands: relations to movement stability and optimality.

The framework of the uncontrolled manifold (UCM) hypothesis was used to explore variables related to stability of task performance in the two hands of young healthy individuals. Fourteen young adults performed four-finger accurate constant force production tasks interrupted by a voluntary quick force pulse production and by an externally imposed displacement of all fingers. Three groups of variables were used to quantify stability of steady force production: (1) indices of the inter-trial variance were computed within the UCM and orthogonal to the UCM; (2) indices of motor equivalence were computed between steady-state intervals separated by the force pulse and by the finger-lifting episode; and (3) referent coordinate and apparent stiffness were computed using the data during the ascending phase of the finger-lifting episode. In another task, the subjects performed accurate constant force production with visual feedback removal after the 8th second, and the drop in the total force after the removal was computed. There were differences between the right and left hand in some outcome variables such as variance within the UCM, and the timing of anticipatory synergy adjustments prior to the force pulse, consistent with the dynamic dominance hypothesis. There were significant correlations between the two hands for indices that were unrelated to accuracy of performance: variance within the UCM, index of motor equivalence, referent coordinate, apparent stiffness, and the drop of total force after visual feedback removal. We interpret these findings within the concept of stability-optimality trade-off. In particular, we conclude that individual subjects select particular, person-specific solutions within the spectrum allowed by the explicit task constraints, and this choice is consistent between the two hands. We conclude with a hypothesis that selecting specific solutions within the stability-optimality trade-off may represent an individual's personal preference consistent between the two hands.

Quantitative analysis of multi-element synergy stabilizing performance: comparison of three methods with respect to their use in clinical studies.

A number of analyses associated with the uncontrolled manifold (UCM) hypothesis have been used recently to investigate stability of actions across populations. We explored whether some of those methods have an advantage for clinical studies because they require fewer trials to achieve consistent findings. We compared the number of trials needed for the analysis of inter-trial variance, analysis of motor equivalence, and analysis in the space of referent coordinates. Young healthy adults performed four-finger accurate force production tasks under visual feedback with the right (dominant) and left hand over three days. Three methods [analytical (M1), experimental (M2), and cumulative mean (M3) methods] were used to define the minimal number of trials required to reach certain statistical criteria. Two of these methods, M1 and M2, showed qualitatively similar results. Fewer trials (M1: 5-13, M2: 4-10) were needed for analysis of motor equivalence compared to inter-trial variance analysis (M1: 14-24, M2: 10-14). The third method (M3) showed no major differences among the outcome variables. The index of synergy in the inter-trial variance analysis required a very small number of trials (M1, M2: 2-4). Variables related to referent coordinates required only a few trials (under 3), whereas the synergy index in this analysis required the largest number of trials (M1: 24-34, M2: 12-16). This is the first study to quantify the number of trials needed for UCM-based methods of assessing motor coordination broadly used in clinical studies. Clinical studies can take advantage of specific recommendations based on the current data regarding the number of trials needed for each analysis thus allowing minimizing the test session duration without compromising data reliability.

Distinct progression pattern of susceptibility MRI in the substantia nigra of Parkinson's patients.

BACKGROUND: Susceptibility MRI may capture Parkinson's disease-related pathology. This study delineated longitudinal changes in different substantia nigra regions. METHODS: Seventy-two PD patients and 62 controls were studied at both baseline and after 18 months with MRI. R2* and quantitative susceptibility mapping values from the substantia nigra pars compacta and substantia nigra pars reticulata were calculated. Mixed-effects models compared controls with PD or PD subgroups having different disease durations: early (<1 year), middle (<5 years, middle-stage PD), and late (>5 years, late-stage PD). Pearson's correlation assessed associations between imaging and clinical measures. RESULTS: At baseline, R2* and quantitative susceptibility mapping were higher in both the substantia nigra pars compacta and substantia nigra pars reticulata in all PD patients (group effect, P ≤ 0.003). Longitudinally, the substantia nigra pars compacta R2* showed a faster increase in PD compared with controls (time × group, P = 0.002), whereas quantitative susceptibility mapping did not (P = 0.668). The substantia nigra pars reticulata R2* and quantitative susceptibility mapping did not differ between PD and controls (time × group, P ≥ 0.084), although both decreased longitudinally (time effect, P ≤ 0.004). Baseline substantia nigra pars compacta R2* was higher in all PD subgroups (group, P ≤ 0.006), but showed a significantly faster increase only in later-stage PD (time × group, P < 0.0001) that correlated with changes in nonmotor symptoms (r = 0.746, P = 0.002). Baseline substantia nigra pars reticulata quantitative susceptibility mapping was higher in middle-stage PD and later-stage PD (group, P ≤ 0.002), but showed a longitudinal decrease (time × group, P = 0.004) only in later-stage PD that correlated with changes in motor signs (r = 0.837, P < 0.001). CONCLUSION: Susceptibility MRI revealed distinct patterns of PD progression in the substantia nigra pars compacta and substantia nigra pars reticulata. The different patterns are particularly clear in later-stage patients. These findings may resolve past controversies and have implications in the pathophysiological processes during PD progression. © 2018 International Parkinson and Movement Disorder Society.

Susceptibility MRI captures nigral pathology in patients with parkinsonian syndromes.

BACKGROUND: Parkinsonisms are neurodegenerative disorders characterized pathologically by α-synuclein-positive (e.g., PD, diffuse Lewy body disease, and MSA) and/or tau-positive (e.g., PSP, cortical basal degeneration) pathology. Using R2* and quantitative susceptibility mapping, susceptibility changes have been reported in the midbrain of living parkinsonian patients, although the exact underlying pathology of these alterations is unknown. OBJECTIVE: The current study investigated the pathological correlates of these susceptibility MRI measures. METHODS: In vivo MRIs (T1- and T2-weighted, and T2*) and pathology were obtained from 14 subjects enrolled in an NINDS PD Biomarker Program (PDBP). We assessed R2* and quantitative susceptibility mapping values in the SN, semiquantitative α-synuclein, tau, and iron values, as well as neuronal and glial counts. Data were analyzed using age-adjusted Spearman correlations. RESULTS: R2* was associated significantly with nigral α-synuclein (r = 0.746; P = 0.003). Quantitative susceptibility mapping correlated significantly with Perls' (r = 0.758; P = 0.003), but not with other pathological measurements. Neither measurement correlated with tau or glial cell counts (r ≤ 0.11; P ≥ 0.129). CONCLUSIONS: Susceptibility MRI measurements capture nigral pathologies associated with parkinsonian syndromes. Whereas quantitative susceptibility mapping is more sensitive to iron, R2* may reflect pathological aspects of the disorders beyond iron such as α-synuclein. They may be invaluable tools in diagnosing differential parkinsonian syndromes, and tracking in living patients the dynamic changes associated with the pathological progression of these disorders. © 2018 International Parkinson and Movement Disorder Society.

Stability of steady hand force production explored across spaces and methods of analysis.

We used the framework of the uncontrolled manifold (UCM) hypothesis and explored the reliability of several outcome variables across different spaces of analysis during a very simple four-finger accurate force production task. Fourteen healthy, young adults performed the accurate force production task with each hand on 3 days. Small spatial finger perturbations were generated by the "inverse piano" device three times per trial (lifting the fingers 1 cm/0.5 s and lowering them). The data were analyzed using the following main methods: (1) computation of indices of the structure of inter-trial variance and motor equivalence in the space of finger forces and finger modes, and (2) analysis of referent coordinates and apparent stiffness values for the hand. Maximal voluntary force and the index of enslaving (unintentional finger force production) showed good to excellent reliability. Strong synergies stabilizing total force were reflected in both structure of variance and motor equivalence indices. Variance within the UCM and the index of motor equivalent motion dropped over the trial duration and showed good to excellent reliability. Variance orthogonal to the UCM and the index of non-motor equivalent motion dropped over the 3 days and showed poor to moderate reliability. Referent coordinate and apparent stiffness indices co-varied strongly and both showed good reliability. In contrast, the computed index of force stabilization showed poor reliability. The findings are interpreted within the scheme of neural control with referent coordinates involving the hierarchy of two basic commands, the r-command and c-command. The data suggest natural drifts in the finger force space, particularly within the UCM. We interpret these drifts as reflections of a trade-off between stability and optimization of action. The implications of these findings for the UCM framework and future clinical applications are explored in the discussion. Indices of the structure of variance and motor equivalence show good reliability and can be recommended for applied studies.

Statins may facilitate Parkinson's disease: Insight gained from a large, national claims database.

OBJECTIVE: Using a large U.S. claims database (MarketScan), we investigated the controversy surrounding the role of statins in Parkinson's disease (PD). METHODS: We performed a retrospective case-control analysis. First, we identified 2322 incident PD cases having a minimum of 2.5 years of continuous enrollment prior to earliest diagnosis code or prescription of antiparkinson medication. A total of 2322 controls were then matched individually by age, gender, and a follow-up window to explore the relationship of statin use with incident PD. RESULTS: Statin usage was significantly associated with PD risk, with the strongest associations being for lipophilic (odds ratio = 1.58, P < .0001) versus hydrophilic (odds ratio = 1.19, P = .25) statins, statins plus nonstatins (odds ratio = 1.95, P < .0001), and for the initial period after starting statins (<1 year odds ratio = 1.82, 1-2.5 years odds ratio = 1.75, and ≥2.5 years odds ratio = 1.37; Ptrend < .0001). CONCLUSION: The use of statin (especially lipophilics) was associated with higher risk of PD, and the stronger association in initial use suggests a facilitating effect. © 2017 International Parkinson and Movement Disorder Society.

Free water improves detection of changes in the substantia nigra in parkinsonism: A multisite study.

BACKGROUND: Imaging markers that are sensitive to parkinsonism across multiple sites are critically needed for clinical trials. The objective of this study was to evaluate changes in the substantia nigra using single- and bi-tensor models of diffusion magnetic resonance imaging in PD, MSA, and PSP. METHODS: The study cohort (n = 425) included 107 healthy controls and 184 PD, 63 MSA, and 71 PSP patients from 3 movement disorder centers. Bi-tensor free water, free-water-corrected fractional anisotropy, free-water-corrected mean diffusivity, single-tensor fractional anisotropy, and single-tensor mean diffusivity were computed for the anterior and posterior substantia nigra. Correlations were computed between diffusion MRI measures and clinical measures. RESULTS: In the posterior substantia nigra, free water was greater for PSP than MSA and PD patients and controls. PD and MSA both had greater free water than controls. Free-water-corrected fractional anisotropy values were greater for PSP patents than for controls and PD patients. PSP and MSA patient single-tensor mean diffusivity values were greater than controls, and single-tensor fractional anisotropy values were lower for PSP patients than for healthy controls. The parkinsonism effect size for free water was 0.145 in the posterior substantia nigra and 0.072 for single-tensor mean diffusivity. The direction of correlations between single-tensor mean diffusivity and free-water values and clinical scores was similar at each site. CONCLUSIONS: Free-water values in the posterior substantia nigra provide a consistent pattern of findings across patients with PD, MSA, and PSP in a large cohort across 3 sites. Free water in the posterior substantia nigra relates to clinical measures of motor and cognitive symptoms in a large cohort of parkinsonism. © 2017 International Parkinson and Movement Disorder Society.

Predicting the multi-domain progression of Parkinson's disease: a Bayesian multivariate generalized linear mixed-effect model.

BACKGROUND: It is challenging for current statistical models to predict clinical progression of Parkinson's disease (PD) because of the involvement of multi-domains and longitudinal data. METHODS: Past univariate longitudinal or multivariate analyses from cross-sectional trials have limited power to predict individual outcomes or a single moment. The multivariate generalized linear mixed-effect model (GLMM) under the Bayesian framework was proposed to study multi-domain longitudinal outcomes obtained at baseline, 18-, and 36-month. The outcomes included motor, non-motor, and postural instability scores from the MDS-UPDRS, and demographic and standardized clinical data were utilized as covariates. The dynamic prediction was performed for both internal and external subjects using the samples from the posterior distributions of the parameter estimates and random effects, and also the predictive accuracy was evaluated based on the root of mean square error (RMSE), absolute bias (AB) and the area under the receiver operating characteristic (ROC) curve. RESULTS: First, our prediction model identified clinical data that were differentially associated with motor, non-motor, and postural stability scores. Second, the predictive accuracy of our model for the training data was assessed, and improved prediction was gained in particularly for non-motor (RMSE and AB: 2.89 and 2.20) compared to univariate analysis (RMSE and AB: 3.04 and 2.35). Third, the individual-level predictions of longitudinal trajectories for the testing data were performed, with ~80% observed values falling within the 95% credible intervals. CONCLUSIONS: Multivariate general mixed models hold promise to predict clinical progression of individual outcomes in PD. TRIAL REGISTRATION: The data was obtained from Dr. Xuemei Huang's NIH grant R01 NS060722 , part of NINDS PD Biomarker Program (PDBP). All data was entered within 24 h of collection to the Data Management Repository (DMR), which is publically available ( https://pdbp.ninds.nih.gov/data-management ).

Motor equivalence and structure of variance: multi-muscle postural synergies in Parkinson's disease.

We explored posture-stabilizing multi-muscle synergies with two methods of analysis of multi-element, abundant systems: (1) Analysis of inter-cycle variance; and (2) Analysis of motor equivalence, both quantified within the framework of the uncontrolled manifold (UCM) hypothesis. Data collected in two earlier studies of patients with Parkinson's disease (PD) were re-analyzed. One study compared synergies in the space of muscle modes (muscle groups with parallel scaling of activation) during tasks performed by early-stage PD patients and controls. The other study explored the effects of dopaminergic medication on multi-muscle-mode synergies. Inter-cycle variance and absolute magnitude of the center of pressure displacement across consecutive cycles were quantified during voluntary whole-body sway within the UCM and orthogonal to the UCM space. The patients showed smaller indices of variance within the UCM and motor equivalence compared to controls. The indices were also smaller in the off-drug compared to on-drug condition. There were strong across-subject correlations between the inter-cycle variance within/orthogonal to the UCM and motor equivalent/non-motor equivalent displacements. This study has shown that, at least for cyclical tasks, analysis of variance and analysis of motor equivalence lead to metrics of stability that correlate with each other and show similar effects of disease and medication. These results show, for the first time, intimate links between indices of variance and motor equivalence. They suggest that analysis of motor equivalence, which requires only a handful of trials, could be used broadly in the field of motor disorders to analyze problems with action stability.

Quantitative susceptibility mapping of the midbrain in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is marked pathologically by dopamine neuron loss and iron overload in the substantia nigra pars compacta. Midbrain iron content is reported to be increased in PD based on magnetic resonance imaging (MRI) R2* changes. Because quantitative susceptibility mapping is a novel MRI approach to measure iron content, we compared it with R2* for assessing midbrain changes in PD. METHODS: Quantitative susceptibility mapping and R2* maps were obtained from 47 PD patients and 47 healthy controls. Midbrain susceptibility and R2* values were analyzed by using both voxel-based and region-of-interest approaches in normalized space, and analyzed along with clinical data, including disease duration, Unified Parkinson's Disease Rating Scale (UPDRS) I, II, and III subscores, and levodopa-equivalent daily dosage. All studies were done while PD patients were "on drug." RESULTS: Compared with controls, PD patients showed significantly increased susceptibility values in both right (cluster size = 106 mm(3)) and left (164 mm(3)) midbrain, located ventrolateral to the red nucleus that corresponded to the substantia nigra pars compacta. Susceptibility values in this region were correlated significantly with disease duration, UPDRS II, and levodopa-equivalent daily dosage. Conversely, R2* was increased significantly only in a much smaller region (62 mm(3)) of the left lateral substantia nigra pars compacta and was not significantly correlated with clinical parameters. CONCLUSION: The use of quantitative susceptibility mapping demonstrated marked nigral changes that correlated with clinical PD status more sensitively than R2*. These data suggest that quantitative susceptibility mapping may be a superior imaging biomarker to R2* for estimating brain iron levels in PD.