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1.  Postural Sway as a Marker of Progression in Parkinson's disease: a Pilot Longitudinal Study 
Gait & posture  2012;36(3):471-476.
Objective measures of postural control that are sensitive to Parkinson's Disease (PD) progression would improve patient care and accelerate clinical trials. Although measures of postural sway during quiet stance in untreated PD have been shown to differ from age-matched control subjects, it is not known if sway measures change with disease progression in early PD. In this pilot study, we asked whether accelerometer-based metrics of sway could provide a practical tool for monitoring progression of postural dyscontrol in people with untreated or newly treated PD.
We examined 13 subjects with PD and 12 healthy, age-matched control subjects. The PD subjects had been recently diagnosed and had not started any antiparkinsonian medications at the baseline session. All subjects were tested 3-to-6 months and 12 months after the baseline session. Subjects were asked to stand quietly for two minutes while wearing an inertial sensor on their posterior trunk that measured trunk linear acceleration.
Our results suggested that objective sway measures deteriorated over one year despite minimal changes in UPDRS motor scores. Medio-lateral (ML) sway measures were more sensitive than antero-posterior sway measures in detecting progression. The ML JERK was larger in the PD group than the control group across all three testing sessions. The ML sway dispersion and ML sway velocity were also significantly higher in PD compared to control subjects by the 12-month evaluation. It is feasible to measure progression of PD prior to onset of treatment using accelerometer-based measures of quiet standing.
doi:10.1016/j.gaitpost.2012.04.010
PMCID: PMC3894847  PMID: 22750016
Parkinson's disease progression; posture; accelerometry
2.  Are high doses of carbidopa a concern? A randomized clinical trial in Parkinson’s disease 
Background
Recommended doses of carbidopa are 75–200 mg/day. Higher doses could inhibit brain aromatic amino acid decarboxylase and reduce clinical effects.
Methods
We compared 4-week outpatient treatments with carbidopa 75 mg and 450 mg/day administered with levodopa on the subjects’ normal schedule. After each treatment phase subjects had two 2-hour levodopa infusions. The first infusion examined the effects of carbidopa doses administered the preceding four weeks and the second infusion determined the acute effects of the two dosages of carbidopa. The antiparkinsonian effects and levodopa and carbidopa plasma concentrations were monitored during the infusions.
Results
Twelve subjects completed the study. Carbidopa concentrations were eight times higher after the high carbidopa phase. Area under the curve (AUC) for clinical ratings did not differ for the four levodopa infusions although AUC for plasma levodopa was modestly increased with 450 mg of carbidopa. Nine subjects reported the high carbidopa outpatient phase was associated with greater response to levodopa.
Conclusion
Doses of 450 mg/day of carbidopa did not reduce the responses to levodopa infusion, extending the safe range of carbidopa to 450 mg/day.
doi:10.1002/mds.24998
PMCID: PMC3707928  PMID: 22508376
Carbidopa; levodopa; Parkinson’s disease
3.  Effects of a NR2B Selective NMDA Glutamate Antagonist, CP-101,606, on Dyskinesia and Parkinsonism 
Movement Disorders  2008;23(13):1860-1866.
Glutamate antagonists decrease dyskinesia and augment the antiparkinsonian effects of levodopa in animal models of Parkinson’s disease (PD). In a randomized, double-blind, placebo-controlled clinical trial we investigated the acute effects of placebo and two doses of a NR2B subunit selective NMDA glutamate antagonist, CP-101,606, on the response to two-hour levodopa infusions in 12 PD subjects with motor fluctuations and dyskinesia. Both doses of CP-101,606 reduced the maximum severity of levodopa-induced dyskinesia approximately 30% but neither dose improved parkinsonism. CP-101,606 was associated with a dose-related dissociation and amnesia. These results support the hypothesis that glutamate antagonists may be useful antidyskinetic agents. However, future studies will have to determine if the benefits of dyskinesia suppression can be achieved without adverse cognitive effects.
doi:10.1002/mds.22169
PMCID: PMC3390310  PMID: 18759356
Parkinson’s disease; levodopa; dyskinesia; NR2B subunit selective glutamate antagonist; CP-101,606; amnesia; dissociation
4.  Knee Trembling During Freezing of Gait Represents Multiple Anticipatory Postural Adjustments 
Experimental neurology  2008;215(2):334-341.
Freezing of gait (FoG) is an episodic, brief inability to step that delays gait initiation or interrupts ongoing gait. FoG is often associated with an alternating shaking of the knees, clinically referred to as knee trembling or trembling in place. The pathophysiology of FoG and of the concomitant trembling knees is unknown; impaired postural adjustment in preparation for stepping is one hypothesis. We examined anticipatory postural adjustments (APAs) prior to protective steps induced by a forward loss of balance in 10 Parkinson’s disease (PD) subjects with marked FoG and in 10 control subjects. The amplitude and timing of the APAs were determined from changes in the vertical ground-reaction forces recorded by a force plate under each foot and were confirmed by electromyographic recordings of bilateral medial gastrocnemius, tibialis anterior and tensor fascia latae muscles. Protective steps were accomplished with a single APA followed by a step for control subjects, whereas PD subjects frequently exhibited multiple, alternating APAs coexistent with the knee trembling commonly observed during FoG as well as delayed, inadequate or no stepping. These multiple APAs were not delayed in onset and were of similar or larger amplitude than the single APAs exhibited by the control subjects. These observations suggest that multiple APAs produce the knee trembling commonly associated with FoG and that FoG associated with a forward loss of balance is caused by an inability to couple a normal APA to the stepping motor pattern.
doi:10.1016/j.expneurol.2008.10.019
PMCID: PMC3141813  PMID: 19061889
freezing of gait; FoG; Parkinson’s disease; balance; anticipatory postural adjustment; gait initiation
5.  FREEZING OF GAIT IS ASSOCIATED WITH A MISMATCH BETWEEN MOTOR IMAGERY AND MOTOR EXECUTION IN NARROW DOORWAYS, NOT WITH FAILURE TO JUDGE DOORWAY PASSABILITY 
Neuropsychologia  2011;49(14):3981-3988.
Background
Many patients with Parkinson’s disease (PD) develop freezing of gait (FoG), which may manifest as a hesitation or “getting stuck” when they attempt to pass through a doorway. In two experiments, we asked whether FoG is associated with (1) a deficit in internal representation of one’s body size with respect to a doorway and (2) a mismatch between imagined and actual walking times when passing through a doorway.
Method
24 subjects with PD (11 with and 13 without FoG) and 10 control subjects of similar age completed two experiments. In the Passability experiment, subjects judged the passability of doorways with different apertures scaled to their body widths. We compared passability estimates across groups. In the Imagery experiment, subjects timed themselves while: (1) imagining walking through doorways of different apertures and from different distances, and (2) actually walking in the same conditions they had just imagined. We compared imagined and actual walking durations across groups and conditions.
Results
In the Passability experiment, the estimated just-passable doorway was wider, relative to body width, in PD subjects than in control subjects, but there was no difference between PD subjects with and without FoG. In the Imagery experiment, subjects in all groups walked more slowly through narrow doorways than though wide doorways, and subjects with FoG walked much more slowly through the narrowest doorways. PD subjects with FoG showed a large discrepancy between actual and imagined time to pass through narrow doorways, unlike PD subjects without FoG and control subjects.
Conclusions
The equivalent passability judgments in PD subjects with and without FoG indicate that FoG is not specifically associated with a deficit in ability to internally represent space with reference to body size. However, the large difference in duration between actual and imagined walking through narrow doorways in subjects with FoG suggests that PD subjects with FoG did not know how much they would slow down to pass through narrow doorways. The observed discrepancy between imagined and actual walking times may point to a specific problem that contributes to the occurrence of FoG. These results also suggest that caution should be used when interpreting brain imaging results from locomotor imagery studies with PD subjects who have FoG.
doi:10.1016/j.neuropsychologia.2011.10.014
PMCID: PMC3260879  PMID: 22027173
Parkinson’s disease; freezing of gait; motor imagery; body schema; internal representation; affordance
6.  “Silly walks” in Parkinson’s disease: unusual presentation of dopaminergic-induced dyskinesias 
doi:10.1002/mds.23667
PMCID: PMC3139772  PMID: 21495073
gait; biphasic dyskinesias; ballism; psychogenic; bizarre
7.  Effects of a Dopamine Agonist on the Pharmacodynamics of Levodopa in Parkinson Disease 
Archives of Neurology  2010;67(1):27-32.
Background
Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood.
Objective
To examine the effects of a dopamine agonist on the motor response to levodopa.
Design
Double-blind, randomized, placebo-controlled, crossover clinical trial.
Setting
Ambulatory academic referral center.
Patients
Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia.
Interventions
Eligible individuals were randomly assigned to receive pramipexole dihydrochloride or placebo for 4 weeks followed by a 2-hour intravenous levodopa infusion on consecutive days at 2 rates and with blinded assessments. They were then crossed over to the alternate oral therapy for 4 weeks followed by levodopa infusion and reassessment.
Main Outcome Measures
Change in finger-tapping speed, measured using the area under the curve (AUC) for finger taps per minute across time; peak finger-tapping speed; duration of response; time to “ON” (defined as a 10% increase in finger-tapping speed above baseline); walking speed; and dyskinesia AUC.
Results
Pramipexole with levodopa infusion increased finger-tapping speed beyond the change in baseline by a mean (SE) of 170 (47.2) per minute×minutes (P=.006) and more than doubled the AUC for finger-tapping speed. Pramipexole increased peak finger-tapping speed by a mean (SE) of 18 (8.5) taps per minute (P=.02) and improved mean (SE) walking speed (15.9 [0.70] vs 18.9 [0.70] seconds, P=.004). Pramipexole prolonged duration of response after levodopa infusion and shortened time to ON. Pramipexole increased mean (SE) baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85] points, P = .05) and peak dyskinesia scores with levodopa infusion.
Conclusions
Pramipexole augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia. When considering a combination of these therapies, an appropriate balance should be maintained regarding gain of motor function vs worsening of dyskinesia.
Trial Registration
clinicaltrials.gov Identifier: NCT00666653
doi:10.1001/archneurol.2009.287
PMCID: PMC3390306  PMID: 20065126
8.  Effect of Low Concentrations of Apomorphine on Parkinsonism in a Randomized, Placebo-Controlled, Crossover Study 
Archives of Neurology  2008;65(2):193-198.
Objective
To determine whether low concentrations of a dopamine agonist worsen parkinsonism, which would suggest that activation of presynaptic dopamine autoreceptors causes a super-off state.
Design
Randomized, double-blind, placebo-controlled, crossover clinical trial.
Setting
Academic movement disorders center.
Patients
Patients with Parkinson disease and motor fluctuations.
Intervention
Fourteen patients with Parkinson disease and motor fluctuations were randomized to receive 1 of 6 possible sequences of placebo, low-dose (sub-threshold) apomorphine hydrochloride, and high-dose (threshold to suprathreshold) apomorphine hydrochloride infusions. Subthreshold doses of apomorphine hydrochloride (12.5 μg/kg/h every 2 hours and 25 μg/kg/h every 2 hours), threshold to suprathreshold doses of apomorphine hydrochloride (50 μg/kg/h every 2 hours and 100 μg/kg/h every 2 hours), and placebo were infused for 4 hours daily for 3 consecutive days.
Main Outcome Measures
Finger and foot tapping rates.
Results
There was no decline in finger or foot tapping rates during the low-dose apomorphine hydrochloride infusions relative to placebo. The high-dose infusions increased foot tapping (P<.001) and trended toward increasing finger tapping compared with placebo infusions.
Conclusions
Subthreshold concentrations of apomorphine did not worsen parkinsonism, suggesting that pre-synaptic dopamine autoreceptors are not important to the motor response in moderate to advanced Parkinson disease.
doi:10.1001/archneurol.2007.58
PMCID: PMC3390309  PMID: 18268187
10.  Errors in Postural Preparation Lead to Increased Choice Reaction Times for Step Initiation in Older Adults 
Background.
This study asked whether older adults were more likely than younger adults to err in the initial direction of their anticipatory postural adjustment (APA) prior to a step (indicating a motor program error), whether initial motor program errors accounted for reaction time differences for step initiation, and whether initial motor program errors were linked to inhibitory failure.
Methods.
In a stepping task with choice reaction time and simple reaction time conditions, we measured forces under the feet to quantify APA onset and step latency and we used body kinematics to quantify forward movement of center of mass and length of first step.
Results.
Trials with APA errors were almost three times as common for older adults as for younger adults, and they were nine times more likely in choice reaction time trials than in simple reaction time trials. In trials with APA errors, step latency was delayed, correlation between APA onset and step latency was diminished, and forward motion of the center of mass prior to the step was increased. Participants with more APA errors tended to have worse Stroop interference scores, regardless of age.
Conclusions.
The results support the hypothesis that findings of slow choice reaction time step initiation in older adults are attributable to inclusion of trials with incorrect initial motor preparation and that these errors are caused by deficits in response inhibition. By extension, the results also suggest that mixing of trials with correct and incorrect initial motor preparation might explain apparent choice reaction time slowing with age in upper limb tasks.
doi:10.1093/gerona/glr054
PMCID: PMC3110912  PMID: 21498431
Aging; CRT; Step initiation; Inhibition; Anticipatory postural adjustment
11.  ASSESSING MOBILITY AT HOME IN PEOPLE WITH EARLY PARKINSON’S DISEASE USING AN INSTRUMENTED TIMED UP AND GO TEST 
Parkinsonism & related disorders  2010;17(4):277-280.
Gait and mobility problems are prominent features of Parkinson’s Disease (PD), and are difficult to observe clinically in early stages of PD. We previously reported that gait changes were measurable in early to mid-stage PD subjects, when we used inertial sensors during an instrumented Timed Up and Go test (iTUG). With the advent of wearable inertial sensors, home assessment of mobility has become possible. We tested six people with early PD and eight control subjects using the iTUG in the home and laboratory. Our objectives were to 1) investigate the feasibility of testing subjects at home, and 2) compare performance at home versus laboratory. We found that home iTUG testing is feasible and the patients with PD were more affected than the healthy control subjects when tested at home.
doi:10.1016/j.parkreldis.2010.08.001
PMCID: PMC2995832  PMID: 20801706
Parkinson’s Disease; home; instrumented; Timed Up and Go
12.  Novel Pathogenic Lrrk2 p.Asn1437His substitution in familial Parkinson’s disease 
Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 C>A (p.Asn1437His) that co-segregates with disease manifestation (LOD=3.15, θ=0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa-responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1/692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP-binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2-linked parkinsonism.
doi:10.1002/mds.23265
PMCID: PMC2970614  PMID: 20669305
LRRK2; Parkinson’s disease; genetic; kinase
13.  Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease(Podcast)(e–Pub ahead of print)(LOE Classification) 
Neurology  2010;75(14):1263-1269.
Objective:
To investigate if a central cholinesterase inhibitor will reduce falling frequency in subjects with Parkinson disease (PD) with advanced postural instability.
Background:
Falling due to postural instability is a significant problem in advancing PD, and is minimally impacted by dopaminergic therapy. Anticholinergic medications increase falling in the elderly. Further, CNS cholinergic neuron loss occurs in PD. We hypothesized that acetylcholine augmentation may reduce frequent falling in subjects with PD.
Methods:
We enrolled 23 subjects with PD who reported falling or nearly falling more than 2 times per week. In a randomized, placebo-controlled, crossover design, subjects were given 6 weeks of donepezil or placebo with a 3-week washout between phases. The primary outcomes were daily falls and near falls reported on postcards. Secondary outcomes included scores on the Activities of Balance Confidence Scale, Berg Balance Scale, Clinical Global Impression of Change, Folstein Mini-Mental State Examination, and the motor section of the Unified Parkinson's Disease Rating Scale.
Results:
Fall frequency per day on placebo was 0.25 ± 0.08 (SEM) compared with 0.13 ± 0.03 on donepezil (p < 0.05). The frequency of near falls was not significantly different between phases. The secondary outcomes did not differ; however, there was a trend to improvement on the subject-completed Global Impression of Change scale.
Conclusions:
Subjects with PD fell approximately half as often during the 6 weeks on donepezil than on placebo. Larger trials of cholinergic augmentation are warranted in subjects with PD with frequent falls.
Classification of evidence:
This study provides Class II evidence that donepezil (maximum 10 mg per day) significantly reduced the number of falls in patients with PD (0.13 falls/day, SEM = 0.03) than when taking placebo (0.25 falls/day, SEM = 0.08, p = 0.049).
GLOSSARY
= nucleus basalis of Meynert;
= Mini-Mental State Examination;
= Oregon Health & Sciences University;
= Parkinson disease;
= pedunculopontine nucleus;
= Unified Parkinson's Disease Rating Scale.
doi:10.1212/WNL.0b013e3181f6128c
PMCID: PMC3013493  PMID: 20810998
14.  Preparation for Compensatory Forward Stepping in Parkinson’s Disease 
Objective
To characterize preparation for compensatory stepping in people with Parkinson’s disease (PD) compared with healthy control subjects, and to determine whether levodopa medication improves preparation or the execution phases of the step.
Design
Observational study.
Setting
Outpatient neuroscience laboratory.
Participants
Nineteen participants with idiopathic PD tested both in the on and off levodopa states and 17 healthy subjects.
Intervention
Moveable platform with posterior translations of 24cm at 56cm/s.
Main Outcome Measures
Compensatory steps forward, in response to a backward surface translation (24cm amplitude at 56cm/s), were categorized according to the presence of an anticipatory postural adjustment (APA) before stepping: no APA, single APA, or multiple APAs. The following step parameters were calculated: step latency, step length, center of mass (CoM) average velocity, and CoM displacement at the step initiation.
Results
Lateral APAs were evident in 57% and 42% of trials for people with PD in the off and on medication states, respectively, compared with only 10% of trials for control subjects. Compared with subjects with PD who did not have APAs, those subjects with PD who did make an APA prior to stepping had significantly later (mean ± SEM, 356 ± 16ms vs 305 ± 8ms) and shorter (mean ± SEM, 251 ± 27mm vs 300 ± 16mm) steps, their CoM was significantly farther forward (185 ± 7mm vs 171 ± 5mm) at foot-off, and they took significantly more steps to regain equilibrium. Levodopa did not affect the preparation or execution phase of compensatory stepping. Poor axial scores and reports of freezing in the United Parkinson’s Disease Rating Scale were associated with use of 1 or more APAs before compensatory stepping.
Conclusions
Lateral postural preparation prior to compensatory stepping in subjects with PD was associated with inefficient balance recovery from external perturbations.
doi:10.1016/j.apmr.2010.05.013
PMCID: PMC2950658  PMID: 20801249
Parkinson disease; Rehabilitation
15.  Objective Measurement of Dyskinesia in Parkinson Disease using a Force Plate 
Clinical investigation of levodopa-induced dyskinesia (LID) in Parkinson Disease (PD) is limited because of lack of objective measurements, and no consensus on use of a standard measuring tool. Currently, clinical trials use subject-completed diaries of dyskinesia throughout the day or investigator-administered clinical rating scales. An objective and valid method of measuring LID would reduce bias, variability, and decrease the time and number needed in trials of potential anti-dyskinetic agents. We have investigated using a force plate on which the subject stands which records movement of the center of pressure (CoP) to quantify LID over the course of a levodopa (LD) cycle. 24 PD subjects (17 with LID, 7 without LID) admitted to an inpatient research facility had their anti-parkinsonian meds withheld overnight, and the following morning a 2-hour intravenous LD infusion was administered. The root mean squared of the velocity in the anterior-posterior direction (RMSV) derived from an analysis of the CoP, and a common clinical dyskinesia rating scale (CDRS) were performed repeatedly for 6 hours, initially as subjects were OFF before the LD infusion, through infusion and until OFF again. There was a high correlation between the area under the curve (AUC) of the clinical rating score and the RMSV within and between subjects. As a measure of LID, the RMSV of the CoP had excellent feasibility, validity and reliability.between subjects. Thus, CoP recordings during stance on a force plate can objectively quantify LID in PD and may be very useful in clinical trials or other investigations of dyskinesia.
doi:10.1002/mds.22856
PMCID: PMC3148105  PMID: 20213818
16.  Dyskinesia and the antiparkinsonian response always temporally coincide 
Neurology  2010;74(15):1191-1197.
Objective:
To clinically characterize the temporal relationship between dyskinesia and the antiparkinsonian response when dyskinesia first emerges during long-term levodopa therapy and to determine if it is consistent with the hypothesized mechanism by which dyskinesia develops.
Methods:
Dyskinesia and the antiparkinsonian response to levodopa during 2-hour levodopa infusions were monitored at intervals through the first 4 years of long-term levodopa therapy in 20 subjects with idiopathic Parkinson disease (PD) and previously untreated with levodopa. The onset and offset of the antiparkinsonian response and dyskinesia were compared when dyskinesia first appeared during the 4 years. The findings were compared to 20 subjects with PD on long-term levodopa with dyskinesia and motor fluctuations.
Results:
The onset and offset of the antiparkinsonian response and dyskinesia generally coincided when dyskinesia first appeared during the 4 years and did not suggest any temporal dissociation of the 2 responses. Further, the latency to the onsets of dyskinesia and the antiparkinsonian response tended to shorten during long-term levodopa therapy, suggesting that both responses were sensitized by long-term levodopa.
Conclusions:
The similar onsets and offsets of the antiparkinsonian response and dyskinesia when dyskinesia first appears are not consistent with the postulated progressive decrease in threshold for dyskinesia during long-term levodopa therapy. Other mechanisms for the development of dyskinesia need to be considered.
GLOSSARY
= General Clinical Research Center;
= Oregon Health & Science University;
= Parkinson disease.
doi:10.1212/WNL.0b013e3181d90050
PMCID: PMC2865731  PMID: 20220120
17.  The instrumented Timed Up and Go test: Potential outcome measure for disease modifying therapies in Parkinson's disease 
The Timed Up and Go (TUG) test has been used to assess balance and mobility in Parkinson’s Disease (PD). However, it is not known if this test is sensitive to subtle abnormalities present in early stages of the disease, when balance and gait problems are not clinically evident but may be detected with instrumented analysis of movement. We hypothesize that postural transitions and arm swing during gait will be the most sensitive characteristics of the TUG for early PD. In the present study, we instrumented the TUG test (iTUG) using portable inertial sensors, and extended the walking distance from 3 meters (traditional TUG) to 7 meters. Twelve subjects with early-to-moderate, untreated PD and 12 healthy individuals participated. Our findings show that although the stopwatch measure of TUG duration did not detect abnormalities in early-to-mid stage PD, the peak arm swing velocity on the more affected side, average turning velocity, cadence and peak trunk rotation velocity were significantly slower. These iTUG parameters were also correlated with the UPDRS Motor Scale. Thus, the iTUG test is sensitive to untreated PD and could potentially detect progression of PD and response to symptomatic and disease-modifying treatments.
doi:10.1136/jnnp.2009.173740
PMCID: PMC3065923  PMID: 19726406
Parkinson’s Disease; Timed Up and Go; inertial sensors; gait; postural transitions; untreated
18.  Reduced Performance in Balance, Walking and Turning Tasks is Associated with Increased Neck Tone in Parkinson's Disease 
Experimental neurology  2009;219(2):430-438.
Rigidity or hypertonicity is a cardinal symptom of Parkinson's disease (PD). We hypothesized that hypertonicity of the body axis affects functional performance of tasks involving balance, walking and turning. The magnitude of axial postural tone in the neck, trunk and hip segments of 15 subjects with PD (both ON and OFF levodopa) and 15 control subjects was quantified during unsupported standing in an axial twisting device in our laboratory as resistance to torsional rotation. Subjects also performed six functional tests (walking in a figure of eight [Figure of Eight], Timed Up & Go, Berg Balance Scale, supine rolling task [rollover], Functional Reach, and standing 360-deg turn-in-place) in the ON and OFF state. Results showed that PD subjects had increased tone throughout the axis compared to control subjects (p=0.008) and that this increase was most prominent in the neck. In PD subjects, axial tone was related to functional performance, but most strongly for tone at the neck and accounted for an especially large portion of the variability in the performance of the Figure of Eight test (rOFF=0.68 and rON=0.74, p<0.05) and the Rollover test (rOFF=0.67and rON=0.55, p<0.05). Our results suggest that neck tone plays a significant role in functional mobility and that abnormally high postural tone may be an important contributor to balance and mobility disorders in individuals with PD.
doi:10.1016/j.expneurol.2009.06.013
PMCID: PMC2775914  PMID: 19573528
Parkinson's disease; postural tone; neck tone; functional performance; balance
19.  Association Analysis of MAPT H1 Haplotype and Subhaplotypes in Parkinson’s Disease 
Annals of neurology  2007;62(2):137-144.
Objective
An inversion polymorphism of approximately 900kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene defines two haplotype clades, H1 and H2. Several small case–control studies have observed a marginally significant excess of the H1/H1 diplotype among patients with Parkinson’s disease (PD), and one reported refining the association to a region spanning exons 1 to 4 of MAPT. We sought to replicate these findings.
Methods
We genotyped 1,762 PD patients and 2,010 control subjects for a single nucleotide polymorphism (SNP) that differentiates the H1 and H2 clades. We also analyzed four SNPs that define subhaplotypes within H1 previously reported to associate with PD or other neurodegenerative disorders.
Results
After adjusting for age, sex, and site, we observed a robust association between the H1/H1 diplotype and PD risk (odds ratio for H1/H1 vs H1/H2 and H2/H2, 1.46; 95% confidence interval, 1.25–1.69; p = 8 × 10−7). The effect was evident in both familial and sporadic subgroups, men and women, and early- and late-onset disease. Within H1/H1 individuals, there was no significant difference between cases and control subjects in the overall frequency distribution of H1 subhaplotypes.
Interpretation
Our data provide strong evidence that the H1 clade, which contains MAPT and several other genes, is a risk factor for PD. However, attributing this finding to variants within a specific region of MAPT is premature. Thorough fine-mapping of the H1 clade in large numbers of individuals is now needed to identify the underlying functional variant(s) that alter susceptibility for PD.
doi:10.1002/ana.21157
PMCID: PMC2836920  PMID: 17514749
20.  Lack of evidence for an association between UCHL1 S18Y and Parkinson’s disease 
UCHL1 has been proposed as a candidate gene for Parkinson’s disease (PD). A meta-analysis of white and Asian subjects reported an inverse association between the non-synonymous UCHL1 S18Y polymorphism and PD risk. However, this finding was not replicated in a large case–control study and updated meta-analysis restricted to white subjects. We performed a case–control study of 1757 PD patients recruited from movement disorder clinics and 2016 unrelated controls from four regions of the United States. All subjects self-reported as white. We did not observe evidence for an association between S18Y genotypes and PD (overall P-value for association: P = 0.42). After adjustment for age, sex, and recruitment region, the odds ratio for Y/S versus S/S was 0.91 (95% CI: 0.78–1.06) and for Y/Y versus S/S was 0.87 (95% CI: 0.58–1.29). We also did not observe a significant association for recessive or dominant models of inheritance, or after stratification by age at onset, age at blood draw, sex, family history of PD, or recruitment region. Our results suggest that UCHL1 S18Y is not a major susceptibility factor for PD in white populations although we cannot exclude the possibility that the S18Y variant exerts weak effects on risk, particularly in early-onset disease.
doi:10.1111/j.1468-1331.2007.02012.x
PMCID: PMC2823263  PMID: 18093156
case-control study; neuroepidemiology; Parkinson’s disease; UCHL1
21.  CSF Multianalyte Profile Distinguishes Alzheimer and Parkinson Diseases 
The therapeutic imperative for Alzheimer disease (AD) and Parkinson disease (PD) calls for discovery and validation of biomarkers. Increased cerebrospinal fluid (CSF) τ and decreased amyloid (A) β42 have been validated as biomarkers of AD. In contrast, there is no validated CSF biomarker for PD. We validated our proteomics-discovered multianalyte profile (MAP) in CSF from 95 control subjects, 48 patients with probable AD, and 40 patients with probable PD. An optimal 8-member MAP agreed with expert diagnosis for 90 control subjects (95%), 36 patients with probable AD (75%), and 38 patients with probable PD (95%). This MAP consisted of the following (in decreasing order of contribution): τ, brain-derived neurotrophic factor, interleukin 8, Aβ42, β2-microglobulin, vitamin D binding protein, apolipoprotein (apo) AII, and apoE. This first large-scale validation of a proteomic-discovered MAP suggests a panel of 8 CSF proteins that are highly effective at identifying PD and moderately effective at identifying AD.
doi:10.1309/W01Y0B808EMEH12L
PMCID: PMC2688655  PMID: 18343778
Cerebrospinal fluid; Alzheimer disease; Parkinson disease; Biomarkers; Analyte profile; Random forest algorithm
22.  Can stooped posture explain multidirectional postural instability in patients with Parkinson’s disease? 
To determine the effects of the stooped posture of patients with Parkinson’s disease (PD) on postural stability, we compared the kinetic, kinematic, and electromyographic responses of seven subjects with PD and 11 control subjects to eight directions of surface translations. Control subjects were studied in an upright posture and in a stooped posture that mimicked the posture of the PD subjects. When control subjects adopted a stooped posture, peak center of pressure displacements slowed and decreased, reducing stability margins toward values observed in PD subjects. Stooped control subjects, however, responded to translations with large joint angle displacements, whereas PD subjects exhibited small joint angle displacements. Stooping in control subjects did not lead to abnormally directed horizontal forces under each foot or antagonistic muscle co-activation at the hip and trunk, as seen in PD subjects. Upright and stooped control subjects never fell during the trials, whereas PD subjects fell in 16% of the trials. We conclude that stooped posture is a destabilizing posture, but it does not account for abnormal postural responses in PD.
doi:10.1007/s00221-005-2346-2
PMCID: PMC1351284  PMID: 16096779
Parkinson’s disease; Posture; EMG; Kinematics; Balance
23.  parkin mutation dosage and the phenomenon of anticipation: a molecular genetic study of familial parkinsonism 
BMC Neurology  2005;5:4.
Background
parkin mutations are a common cause of parkinsonism. Possessing two parkin mutations leads to early-onset parkinsonism, while having one mutation may predispose to late-onset disease. This dosage pattern suggests that some parkin families should exhibit intergenerational variation in age at onset resembling anticipation. A subset of familial PD exhibits anticipation, the cause of which is unknown. The aim of this study was to determine if anticipation was due to parkin mutation dosage.
Methods
We studied 19 kindreds that had early-onset parkinsonism in the offspring generation, late-onset parkinsonism in the parent generation, and ≥ 20 years of anticipation. We also studied 28 early-onset parkinsonism cases without anticipation. Patients were diagnosed by neurologists at a movement disorder clinic. parkin analysis included sequencing and dosage analysis of all 12 exons.
Results
Only one of 19 cases had compound parkin mutations, but contrary to our postulate, the affected relative with late-onset parkinsonism did not have a parkin mutation. In effect, none of the anticipation cases could be attributed to parkin. In contrast, 21% of early-onset parkinsonism patients without anticipation had parkin mutations.
Conclusion
Anticipation is not linked to parkin, and may signify a distinct disease entity.
doi:10.1186/1471-2377-5-4
PMCID: PMC551608  PMID: 15725358
24.  Analyzing 180° turns using an inertial system reveals early signs of progress in Parkinson’s Disease 
Changes in turning are one of the early motor deficiencies in Parkinson’s Disease (PD). We have proposed a system based on wearable, inertial sensors and a novel automatic analysis algorithm that can assess 180° turns. Twelve patients in early stages of PD and 14 age-matched healthy subjects were enrolled in this study. Inertial sensors were attached on shanks and sternum. Measurement protocol included walking on a straight pathway, turning 180° and returning back. Subjects were measured 4 times, once every 6 months during an 18 months period. At the baseline, 9 subject from each group repeated the test twice to assess test-retest reliability. Patients with mild PD had a very low Postural Instability Gait Difficulty (PIGD subscore of UPDRS III) score (average 0.67, min 0, max 3). The analysis showed that the patients had a significantly longer turning duration (2.18±0.43 vs. 1.79±0.27, p<0.02) and higher delay in their last step before initiating a turn (0.56±0.04 vs. 0.52±0.04, p<0.03). Estimated turning duration and other metrics had a high test-retest reliability (ρ>0.85). Turning duration also showed a significant Group*Time interaction (p<0.03) during the longitudinal study highlighting early signs of the progression of the disease.
doi:10.1109/IEMBS.2009.5333970
PMCID: PMC2954632  PMID: 19964471
25.  iTUG, a Sensitive and Reliable Measure of Mobility 
Timed Up and Go (TUG) test is a widely used clinical paradigm to evaluate balance and mobility. Although TUG includes several complex subcomponents, namely: sit-to-stand, gait, 180° turn and turn-to-sit; the only outcome is the total time to perform the task. We have proposed an instrumented TUG, called iTUG, using portable inertial sensors to improve TUG in several ways: automatic detection and separation of subcomponents, detailed analysis of each one of them and a higher sensitivity than TUG. Twelve subjects in early stages of Parkinson's Disease (PD) and twelve age matched control subjects were enrolled. Stop-watch measurements did not show a significant difference between the two groups. The iTUG, however, showed a significant difference in cadence between early PD and control subjects (111.1±6.2 vs. 120.4±7.6 step/min, p < 0.006) as well as in angular velocity of arm-swing (123±32.0 vs. 174.0 ± 50.4 °/sec, p < 0.005), turning duration (2.18 ± 0.43 vs. 1.79 ± 0.27 seconds, p < 0.023) and time to perform turn-to-sits (2.96 ± 0.68 vs. 2.40 ± 0.33 seconds, p < 0.023). By repeating the tests for a second time, the test-retest reliability of iTUG was also evaluated. Among the subcomponents of iTUG, gait, turning and turn-to-sit were the most reliable and sit-to-stand was the least reliable.
doi:10.1109/TNSRE.2010.2047606
PMCID: PMC2922011  PMID: 20388604
Gait; balance; mobility; objective assessment; wearable sensors

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