pinecone/core-2020-05-10-deduplication huggingface dataset:
Characterizing freezing of gait in Parkinson's disease: Models of an episodic phenomenon

Freezing of gait (FOG) is a very disabling and common gait disorder in Parkinson's disease (PD). The first aim of this article was to provide a methodological and critical review of the most common research approach to understand FOG, ie, comparing the behavior of freezers with that of non-freezers. The review demonstrates that studies often fall short in clearly defining the freezer\non-freezer groups and in controlling for disease severity and other confounders. These problems complicate data interpretation on FOG. The second aim of this article was to summarize the literature on the potential mechanisms behind the episodic nature of FOG in the following four models: (1) The threshold model assumes that FOG occurs when the accumulation of various motor deficits reinforce each other to a point of motor breakdown; (2) the interference model proposes that FOG represents an inability to deal with concurrent cognitive, limbic, and motor input, causing an interruption of locomotion; (3) the cognitive model views FOG as induced by a failure to process response conflict, leading to behavioral indecision; and (4) the decoupling model sees FOG as a disconnection between preparatory programming and the intended motor response as a result of which automatic movement generation gets stuck. These four theoretical premises are still incomplete and do not fully explain FOG. The depletion of motor and cognitive reserves and an increasingly complex response to levodopa with disease progression will also have an impact on the emergence of FOG episodes. © 2013 International Parkinson and Movement Disorder Society.status: publishe
Dopamine overdose hypothesis: Evidence and clinical implications

About a half a century has passed since dopamine was identified as a neurotransmitter, and it has been several decades since it was established that people with Parkinson's disease receive motor symptom relief from oral levodopa. Despite the evidence that levodopa can reduce motor symptoms, there has been a developing body of literature that dopaminergic therapy can improve cognitive functions in some patients but make them worse in others. Over the past two decades, several laboratories have shown that dopaminergic medications can impair the action of intact neural structures and impair the behaviors associated with these structures. In this review, we consider the evidence that has accumulated in the areas of reversal learning, motor sequence learning, and other cognitive tasks. The purported inverted‐U shaped relationship between dopamine levels and performance is complex and includes many contributory factors. The regional striatal topography of nigrostriatal denervation is a critical factor, as supported by multimodal neuroimaging studies. A patient's individual genotype will determine the relative baseline position on this inverted‐U curve. Dopaminergic pharmacotherapy and individual gene polymorphisms can affect the mesolimbic and prefrontal cortical dopaminergic functions in a comparable, inverted‐U dose‐response relationship. Depending on these factors, a patient can respond positively or negatively to levodopa when performing reversal learning and motor sequence learning tasks. These tasks may continue to be relevant as our society moves to increased technological demands of a digital world that requires newly learned motor sequences and adaptive behaviors to manage daily life activities. © 2013 International Parkinson and Movement Disorder Societ
Driving and off-road impairments underlying failure on road testing in Parkinson's disease

Parkinson's disease (PD) affects driving ability. We aimed to determine the most critical impairments in specific road skills and in clinical characteristics leading to failure on a road test in PD. In this cross-sectional study, certified driving assessment experts evaluated specific driving skills in 104 active, licensed drivers with PD using a standardized, on-road checklist and issued a global decision of pass/fail. Participants also completed an off-road evaluation assessing demographic features, disease characteristics, motor function, vision, and cognition. The most important driving skills and off-road predictors of the pass/fail outcome were identified using multivariate stepwise regression analyses. Eighty-six (65%) passed and 36 (35%) failed the on-road driving evaluation. Persons who failed performed worse on all on-road items. When adjusted for age and gender, poor performances on lateral positioning at low speed, speed adaptations at high speed, and left turning maneuvers yielded the best model that determined the pass/fail decision (R(2)  = 0.56). The fail group performed poorer on all motor, visual, and cognitive tests. Measures of visual scanning, motor severity, PD subtype, visual acuity, executive functions, and divided attention were independent predictors of pass/fail decisions in the multivariate model (R(2)  = 0.60). Our study demonstrated that failure on a road test in PD is determined by impairments in specific driving skills and associated with deficits in motor, visual, executive, and visuospatial functions. These findings point to specific driving and off-road impairments that can be targeted in multimodal rehabilitation programs for drivers with PD. © 2013 International Parkinson and Movement Disorder Society.status: publishe
A noninvasive handheld assistive device to accommodate essential tremor: A pilot study

Background  We explored whether a noninvasive handheld device using Active Cancellation of Tremor (ACT) technology could stabilize tremor‐induced motion of a spoon in individuals with essential tremor (ET).    Methods  Fifteen ET subjects (9 men, 6 women) performed 3 tasks with the ACT device turned on and off. Tremor severity was rated with the Fahn‐Tolosa‐Marin Tremor Rating Scale (TRS). Subjective improvement was rated by subjects with the Clinical Global Impression Scale (CGI‐S). Tremor amplitude was measured using device‐embedded accelerometers in 11 subjects.    Results  TRS scores improved with ACT on (versus off) in all 3 tasks: holding (1.00 ± 0.76 vs. 0.27 ± 0.70;  P  = 0.016), eating (1.47 ± 1.06 vs. 0.13 ± 0.64;  P  = 0.001), and transferring (1.33 ± 0.82 vs. 0.27 ± 0.59;  P  = 0.001). CGI‐S improved with eating and transferring, but not the holding task. Accelerometer measurements demonstrated 71% to 76% reduction in tremor with the ACT device on.    Conclusions  This noninvasive handheld ACT device can reduce tremor amplitude and severity for eating and transferring tasks in individuals with ET. © 2013 International Parkinson and Movement Disorder Societ
Coordinated reset neuromodulation for Parkinson's disease: proof-of-concept study.

The discovery of abnormal synchronization of neuronal activity in the basal ganglia in Parkinson's disease (PD) has prompted the development of novel neuromodulation paradigms. Coordinated reset neuromodulation intends to specifically counteract excessive synchronization and to induce cumulative unlearning of pathological synaptic connectivity and neuronal synchrony.In this prospective case series, six PD patients were evaluated before and after coordinated reset neuromodulation according to a standardized protocol that included both electrophysiological recordings and clinical assessments.Coordinated reset neuromodulation of the subthalamic nucleus (STN) applied to six PD patients in an externalized setting during three stimulation days induced a significant and cumulative reduction of beta band activity that correlated with a significant improvement of motor function.These results highlight the potential effects of coordinated reset neuromodulation of the STN in PD patients and encourage further development of this approach as an alternative to conventional high-frequency deep brain stimulation in PD
Altered corticomotor-cerebellar integrity in young ataxia telangiectasia patients

Magnetic resonance imaging (MRI) research in identifying altered brain structure and function in ataxia-telangiectasia, an autosomal recessive neurodegenerative disorder, is limited. Diffusion-weighted MRI were obtained from 11 ataxia telangiectasia patients (age range, 7-22 years; mean, 12 years) and 11 typically developing age-matched participants (age range, 8-23 years; mean, 13 years). Gray matter volume alterations in patients were compared with those of healthy controls using voxel-based morphometry, whereas tract-based spatial statistics was employed to elucidate white matter microstructure differences between groups. White matter microstructure was probed using quantitative fractional anisotropy and mean diffusivity measures. Reduced gray matter volume in both cerebellar hemispheres and in the precentral-postcentral gyrus in the left cerebral hemisphere was observed in ataxia telangiectasia patients compared with controls (P < 0.05, corrected for multiple comparisons). A significant reduction in fractional anisotropy in the cerebellar hemispheres, anterior/posterior horns of the medulla, cerebral peduncles, and internal capsule white matter, particularly in the left posterior limb of the internal capsule and corona radiata in the left cerebral hemisphere, was observed in patients compared with controls (P< 0.05). Mean diffusivity differences were observed within the left cerebellar hemisphere and the white matter of the superior lobule of the right cerebellar hemisphere (P< 0.05). Cerebellum-localized gray matter changes are seen in young ataxia telangiectasia patients along with white matter tract degeneration projecting from the cerebellum into corticomotor regions. The lack of cortical involvement may reflect early-stage white matter motor pathway degeneration within young patients
Clinical markers for identifying cholinergic deficits in Parkinson's disease

BackgroundCholinergic projection systems degeneration is associated with dopamine nonresponsive features of Parkinson's disease (PD). Cholinergic deficits are variable in nondemented PD. Identification of cholinergic deficits in PD may help with selection of suitable patients for targeted cholinergic drug treatment in PD. The objective of this retrospective multivariate predictor analysis study was to identify clinical markers indicative of cholinergic deficits in PD patients, as assessed by acetylcholinesterase ([11C]PMP) positron emission tomography.MethodsOne hundred thirty‐seven PD patients (34 female) participated; median modified Hoehn and Yahr score was 2.5 (range, 1‐4), average age 65.6 ± 7.4 years, and average duration of motor disease symptoms of 6.0 ± 4.2 years. Subjects were dichotomized as “normocholinergic” or “hypocholinergic” based on a 5th percentile cutoff from normal for the basal forebrain‐cortical and pedunculopontine nucleus‐thalamic cholinergic projection systems. Previously identified clinical indices of cholinergic denervation were used for statistical prediction of cholinergic deficits. Logistic regression determined which risk factors predicted cholinergic deficits. Sensitivity, specificity, and accuracy were determined for the (combinations of) significant predictor variables.ResultsForty‐nine (35.8%) hypocholinergic PD subjects were identified. The combination of rapid eye movement (REM) sleep behavior disorder (RBD) symptoms and fall history showed highest diagnostic accuracy (81.1%) for predicting combined thalamic and cortical cholinergic deficits. A combined assessment of 8.5 m walk time and lower score on the Montreal cognitive assessment scale provided diagnostic accuracy of 80.7% for predicting isolated cortical cholinergic denervation.ConclusionAssessment of clinical indices of cholinergic denervation may be useful for identifying suitable subjects for trials of targeted cholinergic drug treatments in PD. © 2014 International Parkinson and Movement Disorder Societ
Coenzyme Q10 and spinocerebellar ataxias

The aim of this study was to investigate the association between drug exposure and disease severity in SCA types 1, 2, 3 and 6. The Clinical Research Consortium for Spinocerebellar Ataxias (CRC‐SCA) enrolled 319 participants with SCA1, 2, 3, and 6 from 12 medical centers in the United States and repeatedly measured clinical severity by the Scale for Assessment and Rating of Ataxia (SARA), the Unified Huntington's Disease Rating Scale part IV (UHDRS‐IV), and the 9‐item Patient Health Questionnaire during July 2009 to May 2012. We employed generalized estimating equations in regression models to study the longitudinal effects of coenzyme Q10 (CoQ10), statin, and vitamin E on clinical severity of ataxia after adjusting for age, sex, and pathological CAG repeat number. Cross‐sectionally, exposure to CoQ10 was associated with lower SARA and higher UHDRS‐IV scores in SCA1 and 3. No association was found between statins, vitamin E, and clinical outcome. Longitudinally, CoQ10, statins, and vitamin E did not change the rates of clinical deterioration indexed by SARA and UHDRS‐IV scores within 2 years. CoQ10 is associated with better clinical outcome in SCA1 and 3. These drug exposures did not appear to influence clinical progression within 2 years. Further studies are warranted to confirm the association. © 2014 International Parkinson and Movement Disorder Societ
Microstructural changes in white matter associated with freezing of gait in Parkinson’s disease

In Parkinson's disease (PD), freezing of gait (FOG) is associated with widespread functional and structural gray matter changes throughout the brain. Previous study of freezing-related white matter changes was restricted to brainstem and cerebellar locomotor tracts. This study was undertaken to determine the spatial distribution of white matter damage associated with FOG by combining whole brain and striatofrontal seed-based diffusion tensor imaging. Diffusion-weighted images were collected in 26 PD patients and 16 age-matched controls. Parkinson's disease groups with (n = 11) and without freezing of gait (n = 15) were matched for age and disease severity. We applied tract-based spatial statistics to compare fractional anisotropy and mean diffusivity of white matter structure across the whole brain between groups. Probabilistic tractography was used to evaluate fractional anisotropy and mean diffusivity of key subcortico-cortical tracts. Tract-based spatial statistics revealed decreased fractional anisotropy in PD with FOG in bilateral cerebellar and superior longitudinal fascicle clusters. Increased mean diffusivity values were apparent in the right internal capsule, superior frontal cortex, anterior corona radiata, the left anterior thalamic radiation, and cerebellum. Tractography showed consistent white matter alterations in striatofrontal tracts through the putamen, caudate, pallidum, subthalamic nucleus, and in connections of the cerebellar peduncle with subthalamic nucleus and pedunculopontine nucleus bilaterally. We conclude that FOG is associated with diffuse white matter damage involving major cortico-cortical, corticofugal motor, and several striatofrontal tracts in addition to previously described cerebello-pontine connectivity changes. These distributed white matter abnormalities may contribute to the motor and non-motor correlates of FOG. © 2015 International Parkinson and Movement Disorder Society.status: publishe
Automated Neuromelanin Imaging as a Diagnostic Biomarker for Parkinson's Disease

Published onlineWe aimed to analyze the diagnostic accuracy of an automated segmentation and quantification method of the SNc and locus coeruleus (LC) volumes based on neuromelanin (NM)-sensitive MRI (NM-MRI) in patients with idiopathic (iPD) and monogenic (iPD) Parkinson's disease (PD). Thirty-six patients (23 idiopathic and 13 monogenic PARKIN or LRRK2 mutations) and 37 age-matched healthy controls underwent 3T-NM-MRI. SNc and LC volumetry were performed using fully automated multi-image atlas segmentation. The diagnostic performance to differentiate PD from controls was measured using the area under the curve (AUC) and likelihood ratios based on receiver operating characteristic (ROC) analyses. We found a significant reduction of SNc and LC volumes in patients, when compared to controls. ROC analysis showed better diagnostic accuracy when using SNc volume than LC volume. Significant differences between ipsilateral and contralateral SNc volumes, in relation to the more clinically affected side, were found in patients with iPD (P=0.007). Contralateral atrophy in the SNc showed the highest power to discriminate PD subjects from controls (AUC, 0.93-0.94; sensitivity, 91%-92%; specificity, 89%; positive likelihood ratio: 8.4-8.5; negative likelihood ratio: 0.09-0.1 at a single cut-off point). Interval likelihood ratios for contralateral SNc volume improved the diagnostic accuracy of volumetric measurements. SNc and LC volumetry based on NM-MRI resulting from the automated segmentation and quantification technique can yield high diagnostic accuracy for differentiating PD from health and might be an unbiased disease biomarker.Supported by the Fund for Health Research Foundation (FIS-ISCIII), Spanish Ministry of Economy and Competitiveness (reference: PI 13/02211); Spanish Ministry of Science and Innovation SAF2006-10126 (2006-2009), SAF2010-22329-C02-01 (2011-2013), and SAF2013-47939-R (to P.P.); project 061131 from the “Fundació La Marató de TV3” and by the UTE project FIMA, Spain (to P.P.). C.O.d.S. and A.M.B. were supported by Spanish Ministry of Economy and Competitiveness DPI2012-38090-C03-02 and TEC2013-48552-C2-1-R, respectively.Publicad
Novel candidate blood-based transcriptional biomarkers of Machado-Joseph disease

BACKGROUND:
Machado-Joseph disease (or spinocerebellar ataxia type 3) is a late-onset polyglutamine neurodegenerative disorder caused by a mutation in the ATXN3 gene, which encodes for the ubiquitously expressed protein ataxin-3. Previous studies on cell and animal models have suggested that mutated ataxin-3 is involved in transcriptional dysregulation. Starting with a whole-transcriptome profiling of peripheral blood samples from patients and controls, we aimed to confirm abnormal expression profiles in Machado-Joseph disease and to identify promising up-regulated genes as potential candidate biomarkers of disease status.

METHODS:
The Illumina Human V4-HT12 array was used to measure transcriptome-wide gene expression in peripheral blood samples from 12 patients and 12 controls. Technical validation and validation in an independent set of samples were performed by quantitative real-time polymerase chain reaction (PCR).

RESULTS:
Based on the results from the microarray, twenty six genes, found to be up-regulated in patients, were selected for technical validation by quantitative real-time PCR (validation rate of 81% for the up-regulation trend). Fourteen of these were further tested in an independent set of 42 patients and 35 controls; 10 genes maintained the up-regulation trend (FCGR3B, CSR2RA, CLC, TNFSF14, SLA, P2RY13, FPR2, SELPLG, YIPF6, and GPR96); FCGR3B, P2RY13, and SELPLG were significantly up-regulated in patients when compared with controls.

CONCLUSIONS:
Our findings support the hypothesis that mutated ataxin-3 is associated with transcription dysregulation, detectable in peripheral blood cells. Furthermore, this is the first report suggesting a pool of up-regulated genes in Machado-Joseph disease that may have the potential to be used for fine phenotyping of this disease.UK Medical Research Council (MRC)Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BPD/33611/2009Fundação para a Ciência e a Tecnologia (FCT) - project FCOMP-01-0124-FEDER-028753 (PTDC/DTP/PIC/0370/2012)Fundo Regional para a Ciência (FRC), Governo dos Açores - M3.1.2/F/006/2011; M3.1.7/F/031/2011 ; M3.1.3/F/004/2009Operational Competitiveness Programme—COMPET
King's Parkinson's disease pain scale, the first scale for pain in PD: An international validation

Pain is a key unmet need and a major aspect of non‐motor symptoms of Parkinson's disease (PD). No specific validated scales exist to identify and grade the various types of pain in PD. We report an international, cross‐sectional, open, multicenter, one‐point‐in‐time evaluation with retest study of the first PD‐specific pain scale, the King's PD Pain Scale. Its seven domains include 14 items, each item scored by severity (0‐3) multiplied by frequency (0‐4), resulting in a subscore of 0 to 12, with a total possible score range from 0 to 168. One hundred seventy‐eight PD patients with otherwise unexplained pain (age [mean ± SD], 64.38 ± 11.38 y [range, 29‐85]; 62.92% male; duration of disease, 5.40 ± 4.93 y) and 83 nonspousal non‐PD controls, matched by age (64.25 ± 11.10 y) and sex (61.45% males) were studied. No missing data were noted, and floor effect was observed in all domains. The difference between mean and median King's PD Pain Scale total score was less than 10% of the maximum observed value. Skewness was marginally high (1.48 for patients). Factor analysis showed four factors in the King's PD Pain Scale, explaining 57% of the variance (Kaiser‐Mayer‐Olkin, 0.73; sphericity test). Cronbach's alpha was 0.78, item‐total correlation mean value 0.40, and item homogeneity 0.22. Correlation coefficients of the King's PD Pain Scale domains and total score with other pain measures were high. Correlation with the Scale for Outcomes in PD‐Motor, Non‐Motor Symptoms Scale total score, and quality of life measures was high. The King's PD Pain Scale seems to be a reliable and valid scale for grade rating of various types of pain in PD. © 2015 International Parkinson and Movement Disorder Societ
The pedunculopontine tegmental nucleus - A functional hypothesis from the comparative literature

We present data from animal studies showing that the pedunculopontine tegmental nucleus-conserved through evolution, compartmentalized, and with a complex pattern of inputs and outputs-has functions that involve formation and updates of action-outcome associations, attention, and rapid decision making. This is in contrast to previous hypotheses about pedunculopontine function, which has served as a basis for clinical interest in the pedunculopontine in movement disorders. Current animal literature points to it being neither a specifically motor structure nor a master switch for sleep regulation. The pedunculopontine is connected to basal ganglia circuitry but also has primary sensory input across modalities and descending connections to pontomedullary, cerebellar, and spinal motor and autonomic control systems. Functional and anatomical studies in animals suggest strongly that, in addition to the pedunculopontine being an input and output station for the basal ganglia and key regulator of thalamic (and consequently cortical) activity, an additional major function is participation in the generation of actions on the basis of a first-pass analysis of incoming sensory data. Such a function-rapid decision making-has very high adaptive value for any vertebrate. We argue that in developing clinical strategies for treating basal ganglia disorders, it is necessary to take an account of the normal functions of the pedunculopontine. We believe that it is possible to use our hypothesis to explain why pedunculopontine deep brain stimulation used clinically has had variable outcomes in the treatment of parkinsonism motor symptoms and effects on cognitive processing. © 2016 International Parkinson and Movement Disorder Society