Unmedicated Parkinson's Disease Research Articles

Antiparkinsonian medication masks motor signal progression in de novo patients

Patients not yet receiving medication provide insight to drug-naïve early physiology of Parkinson's Disease (PD). Wearable sensors can measure changes in motor features before and after introduction of antiparkinsonian medication. We aimed to identify features of upper limb bradykinesia, postural stability, and gait that measurably progress in de novo PD patients prior to the start of medication, and determine whether these features remain sensitive to progression in the period after commencement of antiparkinsonian medication.Upper limb motion was measured using an inertial sensor worn on a finger, while postural stability and gait were recorded using an array of six wearable sensors. Patients were tested over nine visits at three monthly intervals. The timepoint of start of medication was noted.Three upper limb bradykinetic features (finger tapping speed, pronation supination speed, and pronation supination amplitude) and three gait features (gait speed, arm range of motion, duration of stance phase) were found to progress in unmedicated early-stage PD patients. In all features, progression was masked after the start of medication.Commencing antiparkinsonian medication is known to lead to masking of progression signals in clinical measures in de novo PD patients. In this study, we show that this effect is also observed with digital measures of bradykinetic and gait motor features.

Subthalamic Single Cell and Oscillatory Neural Dynamics of a Dyskinetic Medicated Patient With Parkinson's Disease.

Single cell neuronal activity (SUA) and local field potentials (LFP) in the subthalamic nucleus (STN) of unmedicated Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery have been well-characterized during microelectrode recordings (MER). However, there is limited knowledge about the changes in the firing patterns and oscillations above and within the territories of STN after the intake of dopaminergic medication. Here, for the first time, we report the STN single cell and oscillatory neural dynamics in a medicated patient with idiopathic PD using intraoperative MER. We recorded LFP and SUA with microelectrodes at various depths during bilateral STN-DBS electrode implantation. We isolated 26 neurons in total and observed that tonic and irregular firing patterns of individual neurons predominated throughout the territories of STN. While burst-type firings have been well-characterized in the dorsal territories of STN in unmedicated patients, interestingly, this activity was not observed in our medicated subject. LFP recordings lacked the excessive beta (8–30 Hz) activity, characteristic of the unmedicated state and signal energy was mainly dominated by slow oscillations below 8 Hz. We observed sharp gamma oscillations between 70 and 90 Hz within and above the STN. Despite the presence of a broadband high frequency activity in 200–400 Hz range, no cross-frequency interaction in the form of phase-amplitude coupling was noted between low and high frequency oscillations of LFPs. While our results are in agreement with the previously reported LFP recordings from the DBS lead in medicated PD patients, the sharp gamma peak present throughout the depth recordings and the lack of bursting firings after levodopa intake have not been reported before. The lack of bursting in SUA, the lack of excessive beta activity and cross frequency coupling between HFOs and lower rhythms further validate the link between bursting firing regime of neurons and pathological oscillatory neural activity in PD-STN. Overall, these observations not only validate the existing literature on the PD electrophysiology in healthy/medicated animal models but also provide insights regarding the underlying electro-pathophysiology of levodopa-induced dyskinesias in PD patients through demonstration of multiscale relationships between single cell firings and field potentials.

Peripheral Neuropathy in de novo Patients with Parkinson's Disease.

PurposeThis study aimed to investigate the prevalence of peripheral neuropathy (PNP) and its related serum metabolites in de novo patients with Parkinson's disease (PD). PNP is a type of frequent comorbidity in PD. Although the administration of levodopa has been described as a presumptive risk factor in its development, few studies have explored its effect on unmedicated PD patients.Materials and MethodsThis study included 105 drug-naïve de novo PD patients. A standardized nerve conduction study (NCS) technique was used to evaluate motor or sensory neuropathy. We analyzed serologic tests including metabolic markers of vitamin B12, homocysteine (Hcy), and uric acid (UA).ResultsWe found abnormal nerve conduction velocity findings in 24 out of 105 total patients. Among them, 20 patients showed a type of combined motor-sensory, while three were a type of pure sensory and one was a pure motor. Nine patients had carpal tunnel syndrome. PD with PNP group demonstrated higher serum levels of Hcy and UA compared to PD without PNP group.ConclusionOur data demonstrated a potential role of Hcy and UA on PNP in de novo patients with PD. These results suggest the contribution of the inherent metabolic pathway in deterioration of the peripheral nervous system in PD.

Dopamine replacement remediates risk aversion in Parkinson's disease in a value-independent manner

IntroductionClinical evidence suggests that Parkinson's Disease (PD) patients are risk averse. Dopaminergic therapy has been reported to increase risk tolerance, but the underlying mechanisms are unclear. Some studies have suggested an amplification of subjective reward value, consistent with the role of dopamine in reward value coding. Others have reported value-independent risk enhancement. We evaluated the value-dependence of the effects of PD and its therapy on risk using tasks designed to sensitively measure risk over a wide range of expected values. Method36 patients with idiopathic PD receiving levodopa monotherapy and 36 healthy matched controls performed two behavioural economic tasks aimed at quantifying 1) risk tolerance/aversion in the gain frame and 2) valuation of potential gains relative to losses. PD patients performed the tasks on and off their usual dose of levodopa in randomized order; controls performed the same tasks twice. ResultsRelative to the controls, unmedicated PD patients showed significant value-independent risk aversion in the gain frame, which was normalized by levodopa. PD patients did not differ from controls in their valuation of gains relative to losses. However, across both tasks and regardless of medication, choices of the patients were more determined by expected values of the prospects than those of controls. ConclusionDopamine deficiency in PD was associated with risk aversion, and levodopa promoted riskier choice in a value-independent manner. PD patients also showed an increased sensitivity to expected value, which was independent of levodopa and does not appear to result directly from dopamine deficiency.

Dopamine substitution alters effective connectivity of cortical prefrontal, premotor, and motor regions during complex bimanual finger movements in Parkinson's disease

Bimanual coordination is impaired in Parkinson's disease (PD), affecting patients' quality of life. Besides dysfunction of the basal ganglia network, alterations of cortical oscillatory coupling, particularly between prefrontal and (pre-)motoric areas, are thought to underlie this impairment. Here, we studied 16 PD patients OFF and ON medication and age-matched healthy controls recording high-resolution electroencephalography (EEG) during performance of spatially coupled and uncoupled bimanual finger movements. Dynamic causal modeling (DCM) for induced responses was used to infer task-induced effective connectivity within a network comprising bilateral prefrontal cortex (PFC), lateral premotor cortex (lPM), supplementary motor area (SMA), and primary motor cortex (M1). Performing spatially coupled movements, excitatory left-hemispheric PFC to lPM coupling was significantly stronger in controls compared to unmedicated PD patients. Levodopa-induced enhancement of this connection correlated with increased movement accuracy. During performance of spatially uncoupled movements, PD patients OFF medication exhibited inhibitory connectivity from left PFC to SMA. Levodopa intake diminished these inhibitory influences and restored excitatory PFC to lPM coupling. This restoration, however, did not improve motor function.Concluding, our results indicate that lateralization of prefrontal to premotor connectivity in PD can be augmented by levodopa substitution and is of compensatory nature up to a certain extent of complexity.

Increased putamen hypercapnic vasoreactivity in levodopa-induced dyskinesia

In a rodent model of Parkinson's disease (PD), levodopa-induced involuntary movements have been linked to striatal angiogenesis - a process that is difficult to document in living human subjects. Angiogenesis can be accompanied by localized increases in cerebral blood flow (CBF) responses to hypercapnia. We therefore explored the possibility that, in the absence of levodopa, local hypercapnic CBF responses are abnormally increased in PD patients with levodopa-induced dyskinesias (LID) but not in their nondyskinetic (NLID) counterparts. We used H215O PET to scan 24 unmedicated PD subjects (12 LID and 12 NLID) and 12 matched healthy subjects in the rest state under normocapnic and hypercapnic conditions. Hypercapnic CBF responses were compared to corresponding levodopa responses from the same subjects. Group differences in hypercapnic vasoreactivity were significant only in the posterior putamen, with greater CBF responses in LID subjects compared with the other subjects. Hypercapnic and levodopa-mediated CBF responses measured in this region exhibited distinct associations with disease severity: the former correlated with off-state motor disability ratings but not symptom duration, whereas the latter correlated with symptom duration but not motor disability. These are the first in vivo human findings linking LID to microvascular changes in the basal ganglia.

GPi Oscillatory Activity Differentiates Tics from the Resting State, Voluntary Movements, and the Unmedicated Parkinsonian State.

Background: Deep brain stimulation (DBS) is an emerging treatment strategy for severe, medication-refractory Tourette syndrome (TS). Thalamic (Cm-Pf) and pallidal (including globus pallidus interna, GPi) targets have been the most investigated. While the neurophysiological correlates of Parkinson's disease (PD) in the GPi and subthalamic nucleus (STN) are increasingly recognized, these patterns are not well characterized in other disease states. Recent findings indicate that the cross-frequency coupling (CFC) between beta band and high frequency oscillations (HFOs) within the STN in PD patients is pathologic.Methods: We recorded intraoperative local field potentials (LFPs) from the postero-ventrolateral GPi in three adult patients with TS at rest, during voluntary movements, and during tic activity and compared them to the intraoperative GPi-LFP activity recorded from four unmedicated PD patients at rest.Results: In all PD patients, we noted excessive beta band activity (13–30 Hz) at rest which consistently modulated the amplitude of the co-existent HFOs observed between 200 and 400 Hz, indicating the presence of beta-HFO CFC. In all 3TS patients at rest, we observed theta band activity (4–7 Hz) and HFOs. Two patients had beta band activity, though at lower power than theta oscillations. Tic activity was associated with increased high frequency (200–400 Hz) and gamma band (35–200 Hz) activity. There was no beta-HFO CFC in TS patients at rest. However, CFC between the phase of 5–10 Hz band activity and the amplitude of HFOs was found in two TS patients. During tics, this shifted to CFC between the phase of beta band activity and the amplitude of HFOs in all subjects.Conclusions: To our knowledge this is the first study that shows that beta-HFO CFC exists in the GPi of TS patients during tics and at rest in PD patients, and suggests that this pattern might be specific to pathologic/involuntary movements. Furthermore, our findings suggest that during tics, resting state 5–10 Hz-HFO CFC shifts to beta-HFO CFC which can be used to trigger stimulation in a closed loop system when tics are present.

Ipsilateral deficits of dopaminergic neurotransmission in Parkinson's disease.

The nigral lesion and the resulting contralateral motor signs of Parkinson's disease (PD) are remarkably asymmetric. This study investigated the prevalence of patients with "wrong-sided" lesions, that is, patients with symptoms on the side ipsilateral to the predominant dopaminergic nigrostriatal deficit. The analyzed sample included 434 early unmedicated PD patients from the Parkinson's Progression Markers Initiative database. Asymmetry indices of motor function and putamen [(123)I]FP-CIT SPECT were calculated from the screening visit data. Ipsilateral deficits were unexpectedly common even when only patients with clear motor and dopaminergic asymmetries were included in the analysis (8.1%, n = 24/295). When patients with any asymmetry were included in the analysis, the prevalence of ipsilateral deficits was 15.4% (n = 65/423). Wrong-sided symptoms were not associated with the PD motor subtype. However, the dataset was heavily biased toward tremor-dominant patients (85% of patients). Right-handed PD patients had predominantly right-sided motor symptoms and left-sided dopamine defects, whereas the effect was opposite in left-handed patients (P = 0.005 and 0.028, respectively). The results indicate that the side of the predominant motor symptoms and the corresponding side of the dopaminergic defects in PD are not random, but are directed by brain lateralization. Importantly, the traditional pathogenetic model of nigral degeneration causing primarily contralateral motor symptoms may be inadequate in many patients.

Neuropsychiatric and cognitive symptoms and body side of onset of parkinsonism in unmedicated Parkinson's disease patients.

The onset of motor symptoms is primarily unilateral in the majority of Parkinson's disease (PD) patients. Because of the lateralization of several cognitive and neuropsychiatric functions and the role of impaired dopaminergic transmission on non-motor symptoms in PD, the question raises whether body side of onset of parkinsonian motor symptoms might influence cognitive and/or neuropsychiatric domains in idiopathic PD. Here we investigated the prevalence and severity of neuropsychiatric and cognitive alterations in a cohort of 84 drug naïve PD patients, divided into two groups according to the body side of onset of motor symptoms (42 left onset PD patients-LPD and 42 right onset PD patients-RPD). Eighty-four age-, sex- and educational level-matched healthy subjects (HC) served as controls. Both LPD and RPD patients had higher prevalence and severity of neuropsychiatric and cognitive symptoms with respect to HC. There were no difference between LPD and RPD as to the pattern or severity of neuropsychiatric and cognitive symptoms. However, significantly higher percentage of LPD patients than RPD deviated more than 1.5 SD from mean values of HC at scales for depression. Our results indicate that in early PD patients side of onset of parkinsonian motor symptoms does not influence non-motor accompanying signs, at least at neuropsychiatric and neuropsychological domains, and suggest that differences reported by previous reports may be secondary to disease progression and/or dopamine replacement therapy.

Antisaccades and executive dysfunction in early drug-naive Parkinson's disease: The discovery study.

Cognitive impairment is well recognized in Parkinson's disease (PD), but when it begins to develop is unclear. The aim of this study was to identify early signs of cognitive impairment along with abnormalities in saccadic behavior in newly diagnosed unmedicated PD patients. Nineteen drug-naive PD patients and 20 controls were examined using a battery of tests, including an antisaccade task, phonemic and semantic verbal fluencies, and a switching and rule finding task. With simple tasks, no differences were found between the two groups. However, cognitive performance of the two groups diverged with more complex tasks, occurring independently of PD-related motor impairment. Patients exhibited higher antisaccadic error rates and switch costs in the task switching test, and performed significantly worse in the rule finding task. Certain cognitive domains and saccadic parameters are already significantly impoverished in newly diagnosed Parkinson's patients, even before the initiation of medication.

The onset of nonmotor symptoms in Parkinson's disease (the ONSET PD study).

Nonmotor symptoms (NMS) in Parkinson's disease (PD) can precede onset of motor symptoms. Relationship between premotor symptoms onset and motor features is limited. Our aim is to describe the presence and perceived onset of NMS in PD as well as their possible association with motor phenotype. Presence and onset of NMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls from 11 Spanish and Austrian centers. Seventeen of thirty-one NMS were more common in patients than controls (P < 0.05). They were usually mild and frequently reported to occur at different time-spans before motor symptoms. Anhedonia, apathy, memory complaints, and inattention occurred more frequently during the 2-year premotor period. Those reported more frequently in the 2- to 10-year premotor period were smell loss, mood disturbances, taste loss, excessive sweating, fatigue, and pain. Constipation, dream-enacting behavior, excessive daytime sleepiness, and postprandial fullness were frequently perceived more than 10 years before motor symptoms. No correlation between NMS burden and motor severity, age, or gender was observed. NMS associated in four clusters: rapid eye movement sleep behavior disorder symptoms-constipation, cognition-related, mood-related, and sensory clusters. No cluster was associated with a specific motor phenotype or severity. NMS are common in early unmedicated PD and frequently reported to occur in the premotor period. They are generally mild, but a patient subgroup showed high NMS burden mainly resulting from cognition-related symptoms. Certain NMS when present at the time of assessment or in the premotor stage, either alone or in combination, allowed discriminating PD from controls.

Disturbances in melatonin secretion and circadian sleep–wake regulation in Parkinson disease

ObjectiveUsing salivary dim light melatonin onset (DLMO) and actigraphy, our study sought to determine if Parkinson disease (PD) patients demonstrate circadian disturbance compared to healthy controls. Additionally, our study investigated if circadian disturbances represent a disease-related process or may be attributed to dopaminergic therapy. MethodsTwenty-nine patients with PD were divided into unmedicated and medicated groups and were compared to 27 healthy controls. All participants underwent neurologic assessment and 14days of actigraphy to establish habitual sleep-onset time (HSO). DLMO time and area under the melatonin curve (AUC) were calculated from salivary melatonin sampling. The phase angle of entrainment was calculated by subtracting DLMO from HSO. Overnight polysomnography (PSG) was performed to determine sleep architecture. ResultsDLMO and HSO were not different across the groups. However, the phase angle of entrainment was more than twice as long in the medicated PD group compared to the unmedicated PD group (U=35.5; P=.002) and was more than 50% longer than controls (U=130.0; P=.021). The medicated PD group showed more than double the melatonin AUC compared to the unmedicated group (U=31; P=0.001) and controls (U=87; P=.001). There was no difference in these measures comparing unmedicated PD and controls. ConclusionsIn PD dopaminergic treatment profoundly increases the secretion of melatonin. Our study reported no difference in circadian phase and HSO between groups. However, PD patients treated with dopaminergic therapy unexpectedly showed a delayed sleep onset relative to DLMO, suggesting dopaminergic therapy in PD results in an uncoupling of circadian and sleep regulation.

Factors underlying probabilistic and deterministic stimulus-response learning performance in medicated and unmedicated patients with Parkinson’s disease.

Prior studies have not tested individual differences or effects of medication dosage on stimulus-response learning in patients with Parkinson's disease (PD). In the current study, we investigated the effects of motor variables (including tremor, akinesia, and disease duration) as well as dopaminergic medication dosage on learning in unmedicated PD patients, medicated PD patients, and healthy controls. We tested all subjects on probabilistic and deterministic learning tasks, and also collected awareness measures data using postexperimental questionnaires. Importantly, we tested learning performance in tremor-dominant and akinesia-dominant PD patients, and further correlated learning performance with disease duration and medication dosage. Results show that akinesia-dominant patients were more impaired than tremor-dominant patients at probabilistic reward- but not punishment-based learning, which is in agreement with prior studies of the relationship between akinesia and basal ganglia dysfunction. We also found no difference between medicated and unmedicated PD patients in reward- or punishment-based deterministic learning, but medicated patients were better than unmedicated patients at reward-based probabilistic learning. Our results show that awareness measures explain differences among probabilistic and deterministic learning performance. Moreover, we found that disease duration and motor severity are inversely correlated, and medication dosage is positively correlated, with reward-based probabilistic learning. Our results suggest that stimulus-response learning performance in patients with PD depends on the type of learning (probabilistic vs. deterministic), medication status (on vs. off medication, dopaminergic medication dosage), disease duration as well as motor severity and subtype in PD patients (tremor- vs. akinesia-dominant).

Parkinson's disease cognitive network correlates with caudate dopamine

Prior evidence has suggested a link between caudate dopaminergic functioning and cognition in Parkinson's disease (PD). In this dual tracer study we analyzed the relationship between nigrostriatal dopaminergic dysfunction and the expression of the previously validated PD cognition-related metabolic pattern (PDCP). In this study, 17 non-demented PD patients underwent positron emission tomography (PET) imaging with [(18)F]-fluorodeoxyglucose to measure PDCP expression, and [(18)F]-fluoropropyl-β-CIT (FPCIT) to measure dopamine transporter (DAT) binding. Automated voxel-by-voxel searches of the FPCIT PET volumes were performed to identify regions in which DAT binding significantly correlated with PDCP expression values. The findings were validated using prespecified anatomical regions-of-interest (ROIs). Voxel-wise interrogation of the FPCIT PET scans revealed a single significant cluster in which DAT binding correlated with PDCP expression (p<0.05, corrected). This cluster was localized to the left caudate nucleus; an analogous correlation (r=-0.63, p<0.01) was also present in the "mirror" region of the right hemisphere. These findings were confirmed by the presence of a significant correlation (r=-0.67, p<0.005) between PDCP expression and DAT binding in caudate ROIs, which survived adjustment for age, disease duration, and clinical severity ratings. Correlation between caudate DAT binding and subject expression of the PD motor-related metabolic pattern was not significant (p>0.21). In summary, this study demonstrates a significant relationship between loss of dopaminergic input to the caudate nucleus and the expression of a cognition-related disease network in unmedicated PD patients. These baseline measures likely function in concert to determine the cognitive effects of dopaminergic therapy in PD.

Cognitive slowing in Parkinson's disease is related to frontostriatal dopaminergic dysfunction

BackgroundFrontostriatal and cognitive dysfunctions in Parkinson's disease (PD) are hypothesized to be linked predominately to dopaminergic dysfunction within neural networks linking dorsal striatum to dorsolateral prefrontal cortex. MethodsThe authors evaluated the relationship between frontostriatal dopaminergic function and cognitive performance, especially cognitive processing speed by performing [18F]fluorodopa PET and computerized tests of automatic and controlled cognitive processing speed (CogniSpeed) in 23 newly diagnosed and unmedicated PD patients and 14 controls. ResultsPD patients were slower than the controls in all the CogniSpeed measures studied. The Fdopa uptake in caudate nucleus correlated negatively with slowing on all the tests. Slower performance in relatively automatic processes measured by choice reaction tasks as well as in more controlled processes measured by a calculation task was related to reduced Fdopa uptake in the anterior cingulate gyrus. The reduced dopaminergic function in the thalamus was associated with the slower performance in the subtraction test. ConclusionOur study indicates that dopaminergic dysfunction within neural networks linking striatum to prefrontal cortex is involved in the slowing of both automatic and controlled cognitive processing in PD patients.

Reduced Striatal Dopamine Synthesis Capacity is Associated with Symptoms of Depression in Patients with de novo Unmedicated Parkinson's Disease

Previous studies have suggested that impaired striatal dopamine function might be independently related to depression in patients with Parkinson's disease (PD), but the results are not uniform. In this study, we investigated de novo unmedicated and medicated PD patients with more advanced disease using 18F-fluorodopa-PET. In unmedicated de novo patients, but not in medicated patients, higher depression scores were associated with lower striatal 18F-fluorodopa uptake. These results indicate that impaired striatal dopaminergic function in PD is related to depressive symptoms and that these effects can be observed in de novo patients without the confounding effects of advanced neurodegeneration and medications.

Dissociation between Active and Observational Learning from Positive and Negative Feedback in Parkinsonism

Feedback to both actively performed and observed behaviour allows adaptation of future actions. Positive feedback leads to increased activity of dopamine neurons in the substantia nigra, whereas dopamine neuron activity is decreased following negative feedback. Dopamine level reduction in unmedicated Parkinson’s Disease patients has been shown to lead to a negative learning bias, i.e. enhanced learning from negative feedback. Recent findings suggest that the neural mechanisms of active and observational learning from feedback might differ, with the striatum playing a less prominent role in observational learning. Therefore, it was hypothesized that unmedicated Parkinson’s Disease patients would show a negative learning bias only in active but not in observational learning. In a between-group design, 19 Parkinson’s Disease patients and 40 healthy controls engaged in either an active or an observational probabilistic feedback-learning task. For both tasks, transfer phases aimed to assess the bias to learn better from positive or negative feedback. As expected, actively learning patients showed a negative learning bias, whereas controls learned better from positive feedback. In contrast, no difference between patients and controls emerged for observational learning, with both groups showing better learning from positive feedback. These findings add to neural models of reinforcement-learning by suggesting that dopamine-modulated input to the striatum plays a minor role in observational learning from feedback. Future research will have to elucidate the specific neural underpinnings of observational learning.

Increased risk of leg motor restlessness but not RLS in early Parkinson disease

This study explores the risk and correlates of leg restlessness in drug-naive patients with Parkinson disease (PD) as compared to control subjects matched for age and gender. A total of 200 drug-naive patients with early, unmedicated PD derived from a population-based incident cohort and 173 age- and gender-matched control subjects were assessed for leg restlessness by structured interviews, clinical examination, and blood samples. All subjects were Caucasian. Restless legs syndrome (RLS) was diagnosed according to the essential diagnostic criteria. More patients (81 of 200, 40.5%) than controls (31 of 173, 17.9%) reported leg restlessness (p < 0.001). Thirty-one (15.5%) of these patients with PD and 16 (9.2%) control subjects met RLS criteria (p = 0.07). A total of 21 (12.5%) patients and 12 (6.9%) controls with RLS remained after the exclusion of potential RLS mimics and 26 patients vs 10 control subjects with leg motor restlessness (LMR), leading to a relative risk for RLS of 1.76 (95% confidence interval [CI] 0.90-3.43, p = 0.089) and 2.84 for LMR (95% CI 1.43-5.61, p = 0.001) in PD. Except for increased sleep disturbances in patients with RLS and increased Montgomery and Åsberg Depression Rating Scale scores for patients with RLS or LMR there were no other major differences in relevant blood tests, motor or cognitive function between PD with and without RLS or LMR. LMR and not RLS occurs with a near 3-fold higher risk as compared to controls in early PD. The findings underline a need for more accurate assessments of RLS in PD and support the notion that RLS and PD are different entities.

CSF xanthine, homovanillic acid, and their ratio as biomarkers of Parkinson's disease

Diminished nigrostriatal dopaminergic neurotransmission is a biochemical hallmark of Parkinson's disease. Despite this, a reliable trait biomarker of sporadic Parkinson's disease has not emerged from measurements of cerebrospinal fluid dopamine metabolites. Previous studies have highlighted strong neurochemical relationships between dopamine and various purine compounds. In this study, we analyzed cerebrospinal fluid concentrations of homovanillic acid (the major catabolite of dopamine) and the purine compound xanthine for a comparison of 217 unmedicated Parkinson's disease subjects and 26 healthy controls. These compounds were highly correlated for both the Parkinson's disease subjects (r=0.68) and for controls (r=0.73; both groups, p<0.001). While neither homovanillic acid nor xanthine concentrations differentiated Parkinson's disease from controls, their ratio did. For controls, the mean [xanthine]/[homovanillic acid] quotient was 13.1±5.5 as compared to the Parkinson's disease value of 17.4±6.7 at an initial lumbar CSF collection (p=0.0017), and 19.7±8.7 (p<0.001) at a second CSF collection up to 24months later. The [xanthine]/[homovanillic acid] ratio in the Parkinson's disease subjects differed as a function of disease severity, as measured by the sum of Unified Parkinson's Disease Rating Scale Activities of Daily Living and Motor Exam ratings. The [xanthine]/[homovanillic acid] ratio also increased between the first and second CSF collections, suggesting that this quotient provides both a state and trait biomarker of Parkinson's disease. These observations add to other neurochemical evidence that links purine metabolism to Parkinson's disease.

Drug treatment and familiar music aids an attention shift from vision to somatosensation in Parkinson's disease on the reach-to-eat task

Sensory control of the natural skilled movement of reaching for a food target to eat (reach-to-eat) is closely coupled to the successive phases of the movement. Control subjects visually fixate the target from hand movement onset to the point that the digits contact the food, at which point they look away. This relationship between sensory attention and limb movement suggests that whereas limb advance is under visual control, grasping, limb withdrawal, and releasing the food to the mouth is guided by somatosensation. The pattern of sensory control is altered in Parkinson's disease (PD). PD subjects may visually fixate the target for longer durations prior to movement initiation, during the grasp, and during the initial portion of hand withdrawal suggesting that vision compensates for a somatosensory impairment. Because both medication and listening to favorite musical pieces have been reported to normalize some movements in subjects with PD, the present study compared the effect of medication and listening to preferred musical pieces on sensory attention shifts from vision to somatosensation during the reach-to-eat movement. Biometric measures of eye movement and the movement of the reaching limb were collected from PD subjects and aged-matched control subjects in four conditions in their own homes: off medication, off medication with music, on medication, and on medication with music. Unmedicated PD subjects were slower to visually disengage the target after grasping it. Their disengage latency was shortened by both music and medication. Medication and music did not improve other aspects of reaching, including reaching duration and the ratings of the movement elements of limb advance, grasping, and limb withdrawal. The results are discussed in relation to the idea that one way in which medication and music may aid movement in PD by normalizing somatosensory control of forelimb movement thus reducing compensatory visual monitoring.