Parkinsonism & Related Disorders - Articles in Press

Deep-brain-stimulation does not impair deglutition in Parkinson's disease - Corrected Proof

2012-05-18

Abstract: Objective: A large proportion of patients with Parkinson's disease develop dysphagia during the course of the disease. Dysphagia in Parkinson's disease affects different phases of deglutition, has a strong impact on quality of life and may cause severe complications, i.e. aspirational pneumonia. So far, little is known on how deep-brain-stimulation of the subthalamic nucleus influences deglutition in PD.Methods: Videofluoroscopic swallowing studies on 18 patients with Parkinson's disease, which had been performed preoperatively, and postoperatively with deep-brain-stimulation-on and deep-brain-stimulation-off, were analyzed retrospectively. The patients were examined in each condition with three consistencies (viscous, fluid and solid). The ‘New Zealand Index for Multidisciplinary Evaluation of Swallowing (NZIMES) Subscale One’ for qualitative and ‘Logemann-MBS-Parameters’ for quantitative evaluation were assessed.Results: Preoperatively, none of the patients presented with clinically relevant signs of dysphagia. While postoperatively, the mean daily levodopa equivalent dosage was reduced by 50% and deep-brain-stimulation led to a 50% improvement in motor symptoms measured by the UPDRS III, no clinically relevant influence of deep-brain-stimulation-on swallowing was observed using qualitative parameters (NZIMES). However quantitative parameters (Logemann scale) found significant changes of pharyngeal parameters with deep-brain-stimulation-on as compared to preoperative condition and deep-brain-stimulation-off mostly with fluid consistency.Conclusion: In Parkinson patients without dysphagia deep-brain-stimulation of the subthalamic nucleus modulates the pharyngeal deglutition phase but has no clinically relevant influence on deglutition. Further studies are needed to test if deep-brain-stimulation is a therapeutic option for patients with swallowing disorders.

Sad and happy facial emotion recognition impairment in progressive supranuclear palsy in comparison with Parkinson's disease - Corrected Proof

2012-05-17

Abstract: The severity of motor and non-motor symptoms of progressive supranuclear palsy (PSP) has a profound impact on social interactions of affected individuals and may, consequently, contribute to alter emotion recognition. Here we investigated facial emotion recognition impairment in PSP with respect to Parkinson's disease (PD), with the primary aim of outlining the differences between the two disorders. Moreover, we applied an intensity-dependent paradigm to examine the different threshold of encoding emotional faces in PSP and PD.The Penn Emotion Recognition Test (PERT) was used to assess facial emotion recognition ability in PSP and PD patients. The 2 groups were matched for age, disease duration, global cognition, depression, anxiety, and daily L-Dopa intake.PSP patients displayed significantly lower recognition of sad and happy emotional faces with respect to PD ones. This applied to global recognition, as well as to low-intensity and high-intensity facial emotion recognition.These results indicate specific impairment of recognition of sad and happy facial emotions in PSP with respect to PD patients. The differences may depend upon diverse involvement of cortical–subcortical loops integrating emotional states and cognition between the two conditions, and might represent a neuropsychological correlate of the apathetic syndrome frequently encountered in PSP.

Gaba and serotonin molecular neuroimaging in essential tremor: A clinical correlation study - Corrected Proof

2012-05-17

Abstract: Background: Essential tremor is the most common movement disorder in adults, but its exact etiology and pathophysiology are still not fully understood. There is some consensus, however, about the involvement of the cerebellum and accumulating evidence points towards a dysfunction of the gabaergic system. We hypothesize that the serotonin neurotransmission system may also play a role as it does in tremor in Parkinson disease. This study aimed to investigate the association between the severity of tremor symptoms and the gabaergic and serotoninergic neurotransmission systems in essential tremor.Material and methods: We measured the tremor clinical rating scale score and acquired DASB and Flumazenil PET scans in 10 patients who presented with essential tremor at different stages of clinical severity. Statistically significant correlations were sought between the scale scores and parametric binding potential images.Results: The correlation analysis of cerebellar Flumazenil uptake and tremor clinical rating scale scores reached statistical significance (R2 = 0.423, p = 0.041), whereas no association was detected in the DASB scans.Conclusions: The severity of tremor correlated with the abnormalities found in GABA receptor binding, suggesting a primary gabaergic deficiency or a functional abnormality at the level of GABAA receptor subtypes. These results may assist in the rational development of new pharmacological treatments for essential tremor.

Grey matter volume correlates of cerebrospinal markers of Alzheimer-pathology in Parkinson's disease and related dementia - Corrected Proof

2012-05-17

Abstract: Regional brain grey matter volume (GMV) reductions and abnormal cerebrospinal fluid (CSF) levels of τ and Aβ, extensively studied as biomarkers of Alzheimer's disease (AD), have also been reported in Parkinson's disease (PD) and related dementia (PDD). However, the relationship between these CSF and MRI biomarkers in PD and PDD remains unexplored. We studied these associations in 33 PD patients (18 with no dementia [PDND]; 15 fulfilling PDD criteria) and 12 neurologically unimpaired controls, with neuropsychological assessment, CSF ELISA studies, and voxel-based morphometry (VBM) analysis of high-field brain MRI. Neuropsychological assessment showed a gradation in cognitive performance from controls to PDND (significantly worse on visuospatial performance) and then to PDD (more impaired on memory, naming, fluency and visuospatial functions). No CSF-VBM correlations were found in controls or PDND patients. In contrast, in the analysis of both the PDD subgroup and the entire PD (PDND + PDD) sample, we found significant negative CSF-GMV correlations for τ and phospho-τ and significant positive CSF-GMV correlations for Aβ in mostly frontal and temporal structures. The correlations in the entire PD sample fitted with a linear model and were thus unlikely to have been driven solely by the PDD subgroup. Additionally, an association between both the CSF markers and the CSF-associated GMV reductions with several neuropsychological functions was found. We interpret that CSF markers of AD pathology are associated with VBM-measures of brain atrophy in PD-related dementia and within the PD cognitive continuum, and deserve further attention as putative biomarkers of cognitive impairment and dementia in PD.

Changes in brain glucose metabolism in subthalamic nucleus deep brain stimulation for advanced parkinson's disease - Corrected Proof

2012-05-16

Abstract: Background: Despite its large clinical application, our understanding about the mechanisms of action of deep brain stimulation of the subthalamic nucleus is still limited. Aim of the present study was to explore cortical and subcortical metabolic modulations measured by Positron Emission Tomography associated with improved motor manifestations after deep brain stimulation in Parkinson disease, comparing the ON and OFF conditions.Patients and methods: Investigations were performed in the stimulator off- and on-conditions in 14 parkinsonian patients and results were compared with a group of matched healthy controls. The results were also used to correlate metabolic changes with the clinical effectiveness of the procedure.Results: The comparisons using Statistical parametric mapping revealed a brain metabolic pattern typical of advanced Parkinson disease. The direct comparison in ON vs OFF condition showed mainly an increased metabolism in subthalamic regions, corresponding to the deep brain stimulation site. A positive correlation exists between neurostimulation clinical effectiveness and metabolic differences in ON and OFF state, including the primary sensorimotor, premotor and parietal cortices, anterior cingulate cortex.Conclusion: Deep brain stimulation seems to operate modulating the neuronal network rather than merely exciting or inhibiting basal ganglia nuclei. Correlations with Parkinson Disease cardinal features suggest that the improvement of specific motor signs associated with deep brain stimulation might be explained by the functional modulation, not only in the target region, but also in surrounding and remote connecting areas, resulting in clinically beneficial effects.

Amplitude fluctuations in essential tremor - Corrected Proof

2012-05-16

Abstract: Objective: To assess temporal amplitude variability in patients with essential tremor (ET).Methods: Patients who satisfied the diagnostic criteria for probable or definite ET were enrolled in the study. Each enrolled patient was first rated using The Essential Tremor Rating Assessment Scale (TETRAS). Postural and kinetic tremors of the arms were then measured using a quantitative motor assessment system (QMAS) starting at 8:00AM (T0 – baseline) every 2h for 6h. Subjects were videotaped performing the tasks. Single subjects consecutively performed each assessment twice during every time-interval. At the end of the study, videos were randomized and blindly rated using TETRAS.Results: Twelve ET subjects were enrolled. QMAS and video scores were directly correlated with high test-retest reliability for each time-interval. Furthermore, the QMAS scores at T0 significantly correlated with in-person rated TETRAS scores as well as with subsequent time-intervals instrumental scores. No significant differences were detected between time-intervals QMAS average measurements using ANOVA. There was a maximal 23% absolute variation in tremor amplitude from baseline as determined by the QMAS. Test for equality of variance showed high measurement variability for subjects with high QMAS scores at T0 and throughout the 6h of assessment.Conclusions: Baseline measures are predictive of tremor amplitude at subsequent assessments during the day. High amplitude tremor is associated with high intra-assessment variability.

Epigenetic engineering to reverse the Parkinson’s expression state - Corrected Proof

André X.C.N. Valente, Ricardo Pires das Neves, Paulo J. Oliveira — 2012-05-14

Abstract: Nature, initiation and ensuing cellular propagation mode of sporadic Parkinson’s disease (comprising over 90% of all Parkinson’s cases) remain open research questions. Accordingly, so does the best therapeutic avenue for addressing this debilitating disease that today affects an estimated 7–10 million people worldwide. Recently, we argued that sporadic Parkinson’s be fundamentally characterized as a pathological deviation from normality in the expression program of a cell, the PD-state. Further, we suggested this generic cell state (not restricted to neurons) could be epigenetically locked-in. This raises the theoretical possibility of reverting a cell’s PD-state to normality by appropriate epigenetic reprogramming. In here, we propose an in vitro relatively high throughput search for a cocktail of molecules that induces an epigenetic reversal of the PD-state. A generic multi-tissue PD-state phenotype appears to be a defect on mitochondrial bioenergetics. In the above search, we suggest utilizing a metabolic challenge as a preliminary screen for assessing, via improvement of energy metabolism, reversal of the PD-state.

The relationship between cortical and spinal hyperexcitability and clinical disease severity in stiff-man syndrome - Corrected Proof

Samuel D. Kim, Steve Vucic, Neil Mahant, Matthew C. Kiernan, Victor S.C. Fung — 2012-05-14

Stiff-man syndrome (SMS) is an autoimmune disorder characterised by fluctuating muscular rigidity and spasms, most prominent in axial and proximal limb muscles usually in a symmetric manner. Serum anti-glutamic acid decarboxylase (GAD) antibody is present in 60–80% of patients and there is evidence of both cortical and spinal hyperexcitability, as detected by paired-pulse transcranial magnetic stimulation (TMS) and exteroceptive reflexes, respectively . Significantly, cortical hyperexcitability has been shown to correlate with CSF anti-GAD antibody level , suggesting that anti-GAD antibodies underlie the cortical hyperexcitability, but the relationship between cortical and spinal hyperexcitability and their role in the development of clinical features remain obscure. Therefore, the present study assessed the relationship between cortical and spinal hyperexcitability, and the relationship between either cortical or spinal hyperexcitability and clinical features of SMS.

Muscle selection for treatment of cervical dystonia with botulinum toxin – A systematic review - Corrected Proof

S.W.R. Nijmeijer, J.H.T.M. Koelman, D.J. Kamphuis, M.A.J. Tijssen — 2012-05-10

Abstract: Rationale: Cervical dystonia, also called spasmodic torticollis, is the most common form of (primary) dystonia. Intramuscular injections with botulinum toxin are the first line of treatment for cervical dystonia. To optimise the treatment response to botulinum toxin correct muscles should be selected. Clinical evaluation is important for muscle selection but the value of additional tests to identify dystonic muscles remains unclear.Objective: To evaluate all relevant literature regarding the best approach to select dystonic muscles for treatment with botulinum toxin.Methods: We conducted a systematic review of studies that had investigated methods of selecting muscles for treatment with botulinum toxin. In addition, we compared all prospective botulinum toxin trials using either clinical evaluation or polymyographic electromyography for muscle selection.Results: Forty relevant studies were included and polymyographic electromyography recordings were most often employed. In several studies, polymyographic electromyography revealed a different pattern of muscle involvement compared to that found during clinical evaluation. In one randomized controlled trial polymyographic electromyography significantly improved the outcome of botulinum toxin treatment. A limited number of studies used positron emission tomography – computed tomography imaging or frequency analysis of the electromyography signal to identify dystonic muscles but their effect on the outcome of treatment has never been studied.Conclusion: Polymyographic electromyography may improve the outcome of botulinum toxin treatment in cervical dystonia, but evidence is limited and larger studies are needed.

The alien limb phenomenon and Creutzfeldt–Jakob disease - Corrected Proof

2012-05-10

Abstract: Introduction: Alien limb phenomenon (ALP) has been rarely reported as a presenting feature of Creutzfeldt–Jakob disease (CJD), though neurologists may not recognize it as a prompt to search for CJD.Objective: This report demonstrates the clinical features of patients with ALP and CJD.Methods: All patients with the ALP between 1/1/1996 – 7/28/2011 were identified by the Mayo Clinic Medical Record Linkage system and cross-referenced with a diagnosis of CJD in that same time span. This yielded 13 patients, including six women.Results: The median age at onset of CJD symptoms was 69 years. Two patients were classified as possible CJD, five as probable CJD, and six as definite CJD based on research diagnostic criteria for CJD. The median time to onset of ALP symptoms was 0.5 weeks. The ALP afflicted the left side in nine patients. The median time to death from CJD symptom onset was 10.5 weeks. In four patients ALP was the initial and sole neurologic sign. In four others it was the initial manifestation coexisting with other deficits. ALP related symptoms initially prompted three other patients to seek medical evaluation. ALP was either initially or eventually accompanied by ipsilateral hemineglect, ideomotor apraxia and/or cortical sensory loss in nine patients. Imaging of the contralateral parietal lobe demonstrated cortical T2 hyperintensity and/or restricted diffusion in all eight patients who had abnormal MRI neuroimaging.Conclusions: ALP should trigger suspicion of CJD. The neuroanatomic correlate of ALP in CJD appears to be the contralateral parietal lobe.

Parkinsonian motor features distinguish the agrammatic from logopenic variant of primary progressive aphasia - Corrected Proof

Jonathan Graff-Radford, Joseph R. Duffy, Edythe A. Strand, Keith A. Josephs — 2012-05-10

Abstract: Background: Few studies have assessed parkinsonian motor features across variants of primary progressive aphasia (PPA). Our objective was to compare degree of parkinsonian motor features between two PPA variants.Methods: Parkinsonian motor features were assessed with the Unified Parkinson's Disease Rating scale in prospectively recruited PPA subjects, classified based on recently published criteria. Comparisons across groups were performed with Fisher's exact test for binary data and Mann–Whitney U test for continuous data.Results: Twenty-three PPA subjects were diagnosed with logopenic (n = 11) or nonfluent/agrammatic (n = 12) aphasia. There were no significant differences in illness duration (agrammatic = 3.4 years; logopenic = 3.3 years) or age at onset (nonfluent/agrammatic = 67.3; logopenic = 62.0), but those with logopenic aphasia were more impaired on Mini-Mental State Examination (21.7/30 points vs. 26.1/30; p = 0.04). In contrast, those with logopenic aphasia had fewer parkinsonian motor features than those with agrammatic aphasia (5.7/132 vs. 16.8/132; p = 0.003) which was driven by bradykinesia (p = 0.02) and speech facial/expression (p = 0.04); less so rigidity (p = 0.06). Dysarthria was more frequent in the nonfluent/agrammatic subgroup.Conclusions: Nonfluent/agrammatic subjects have more parkinsonian motor features than logopenic subjects, likely reflecting underlying tau pathology in the agrammatic variant.

Quantitative assessment of the effect of LRRK2 exonic variants on the risk of Parkinson’s disease: A meta-analysis - Corrected Proof

2012-05-10

Abstract: Leucine-rich repeat kinase 2 (LRRK2, PARK8) gene has attracted considerable attention since the variants in this gene are recognized as the most common cause of Parkinson’s disease (PD) so far. A number of association studies concerning variants of LRRK2 gene and PD susceptibility have been conducted in various populations. However, some results were inconclusive. To derive a more precise estimation of the relationship between LRRK2 and genetic risk of PD, we performed a comprehensive meta-analysis which included 27,363 cases and 29,741 controls from 61 published case–control studies. Totally, the effect of five LRRK2 variants all within the coding regions, i.e. G2019S, G2385R, R1628P, P755L and A419V, were evaluated in the meta-analysis using fixed effect model or random effects model if heterogeneity existed. There were genetic associations between four variants (G2019S, G2385R, R1628P and A419V) and increased PD risk, while there was no evidence of statistically significant association between P755L and PD. Publication bias and heterogeneity were absent in most analyses. Within its limitations, this meta-analysis demonstrated that the G2019S, G2385R, R1628P and A419V variations are risk factors associated with increased PD susceptibility. However, these associations vary in different ethnicities.

Cognitive and olfactory deficits in Machado–Joseph disease: A dopamine transporter study - Corrected Proof

2012-05-10

Abstract: Cognitive and olfactory impairments have been demonstrated in patients with Machado–Joseph disease (MJD), and a possible relationship with dopaminergic dysfunction is implicated. However, there is still controversy regarding the pattern of striatal dopaminergic dysfunction in patients with MJD. In this study, we investigated whether these patients had different Dopamine Transporter (DAT) densities as compared to healthy subjects, and correlated these data with cognitive performance and sense of smell. Twenty-two MJD patients and 20 control subjects were enrolled. The neuropsychological assessment comprised the Spatial Span, Symbol Search, Picture Completion, Stroop Color Word Test, Trail Making Test and Phonemic Verbal Fluency test. The 16-item Sniffin' Sticks was used to evaluate odor identification. DAT imaging was performed using the SPECT radioligand [99mTc]-TRODAT-1, alongside with Magnetic Resonance imaging. Patients with MJD showed significantly lower DAT density in the caudate (1.34 ± 0.27 versus 2.02 ± 0.50, p < 0.001), posterior putamen (0.81 ± 0.32 versus 1.32 ± 0.34, p < 0.001) and anterior putamen (1.10 ± 0.31 versus 1.85 ± 0.45, p < 0.001) compared with healthy controls. The putamen/caudate ratio was also significantly lower in patients compared with controls (0.73 ± 0.038 versus 0.85 ± 0.032, p = 0.027). Even though we had only two patients with parkinsonism, we detected striatal dopaminergic deficits in those patients. No significant correlations were detected between DAT density and cognitive performance or Sniffin' Sticks scores. The data suggests that striatal dopamine deficit is not involved in cognitive or sense of smell deficits. This finding raises the possibility of extra-striatal dopamine and other neurotransmitter system involvement or of cerebellum neurodegeneration exerting a direct influence on cognitive and sensorial information processing in MJD.

Meta-analysis on MIBG scintigraphy in differential diagnosis between Parkinson's disease and neurodegenerative parkinsonism - Corrected Proof

Giorgio Treglia, Ernesto Cason — 2012-05-10

We read with great interest the recent article written by Orimo et al. and published online . These distinguished Authors performed an interesting meta-analytic study on the diagnostic performance of Iodine-123 metaiodobenzylguanidine (MIBG) myocardial scintigraphy for differentiating Parkinson's disease (PD) from other neurodegenerative parkinsonism.

A reply to Treglia et al. - Corrected Proof

Satoshi Orimo, Masahiko Suzuki, Akira Inaba, Hidehiro Mizusawa — 2012-05-07

We appreciate the comment by Treglia et al. on our article . We are aware that they have reported the result of a sub-analysis of pooled sensitivity and specificity of MIBG myocardial scintigraphy for differentiating Parkinson's disease (PD) from multiple system atrophy (MSA), and PD from progressive supranuclear palsy (PSP) , and that their result was similar to that of ours . We should have quoted that in our discussion, but unfortunately, we could not do so due to the limited number of words for the text as specified by this journal. Our main focus was to perform a meta-analysis of MIBG myocardial scintigraphy for differentiating PD from other neurodegenerative parkinsonisms, i.e., MSA, PSP, and corticobasal degeneration, which is very important for neurologists in a clinical point of view. Furthermore, we wanted to discuss the pathological background of cardiac MIBG uptake in detail.

Multiple subcutaneous abscesses and necroses due to apomorphine pump treatment - Corrected Proof

Lars Wojtecki, Martin Südmeyer, Alfons Schnitzler — 2012-05-04

Subcutaneous apomorphine therapy is a suitable option for the treatment of motor fluctuations in Parkinson's disease, however even in newer drug formulations skin reactions can be problematic in long term treatment. Skin nodules can occur in up to 70%, panniculitis in 20% and severe forms of these reactions or necroses occur in below 10% of long term treated patients . Recently images were published showing necrotic ulcers as adverse event of subcutaneous apomorphine therapy .

Analysis of colonic alpha-synuclein pathology in multiple system atrophy - Corrected Proof

2012-05-04

Abstract: Routine colonic biopsies allow the detection of alpha-synuclein aggregates in the enteric nervous system (ENS) in living Parkinson's disease (PD) patients. Whether the ENS is affected by alpha-synuclein pathology in multiple system atrophy (MSA) has not been studied yet. The aim of the present research was therefore to analyze colonic biopsies in MSA for the presence of alpha-synuclein pathology. Six MSA and 9 PD patients were included. Four biopsies, taken from the descending colon during the course of a rectosigmoidscopy were microdissected, and analyzed by immunohistochemistry using antibodies against phosphorylated alpha-synuclein and neurofilaments NF 200 kDa. Aggregates of alpha-synuclein were detected in one out of 6 MSA patients and in 5 out of 9 PD patients. This demonstrates that, despite being less frequent than in PD, alpha-synuclein deposits can be observed in the ENS in MSA.

Efficacy of trazodone in antipsychotic-induced akathisia resistant to conventional treatment - Corrected Proof

Roser Ribosa-Nogué, Javier Pagonabarraga, Jaime Kulisevsky — 2012-05-01

Akathisia is characterized by subjective feelings of restlessness and fidgety movements and is a common adverse effect of antipsychotic drugs. Antipsychotic-induced akathisia (AIA) has a prevalence of about 30% in patients taking these drugs and it is severe and disabling in most cases. Early recognition and adequate management are mandatory because AIA has been associated with poor treatment compliance and aggravation of psychotic symptoms, aggressiveness and suicidality.

Patterns of disability, care needs, and quality of life of people with Parkinson’s disease in a general population sample - Corrected Proof

D.L. Terriff, J.V.A. Williams, S.B. Patten, D.H. Lavorato, A.G.M. Bulloch — 2012-04-30

Abstract: Objective: To quantify patterns of disability, care needs, and quality of life in a national community-dwelling sample of people with Parkinson’s disease (PD) in Canada.Methods: Data from Statistics Canada’s Participation and Activity Limitations Survey was used in the analysis. This survey is a post-censual survey that collected data from 28,630 household residents with reported activity limitations in the 2006 Canadian census. Frequencies of specific impairments and care needs as well as mean quality of life ratings were estimated. These estimates were adjusted for age and sex using linear regression modeling. Sampling weights were used to adjust for design effects, ensuring that the estimates were representative of the national population.Results: The estimated prevalence of PD was 0.1% (100 per 100,000 people), consistent with previous estimates. People with PD reported a significantly elevated prevalence of mobility (88.5%), communication (47.9%), pain (68.6%), memory (26.2%) and seeing (47.7%) limitations relative to those with disabilities of other origins. Significantly more people with PD required help with instrumental activities of daily living and activities of daily living. Health related quality of life, measured by the Health Utility Index, was significantly lower in people with PD (mean value 0.46) compared to disabled people without PD (mean value 0.70).Conclusions: People living in the community with PD have a significant burden of disability. Health related quality of life is also quite poor in people with PD compared to other disabled populations. This study helps to quantify the significant care needs of people with PD.

Progressive ataxia and palatal tremor – Two cases with an unusual clinical presentation and course - Corrected Proof

Frank Jan de Jong, Agnita J.W. Boon — 2012-04-30

Progressive ataxia and palatal tremor (PAPT) is a rare neurodegenerative disorder characterized by a slowly progressive ataxia and tremor of the soft palate. MRI-findings show T2-weighted high-signal abnormalities of the inferior olives early in the disease course , although the underlying cause remains unknown . A progressive cerebellar syndrome is usually the only symptomatic feature, although cerebellar ataxia and palatal tremor are often both present at clinical presentation . Here we describe two patients with either ataxia or palatal tremor only at clinical presentation with an unusual disease course during follow-up.

Fall frequency and risk assessment in early Parkinson's disease - Corrected Proof

2012-04-30

Abstract: Background: We sought to define the frequency of falls in early PD and assess potential risk factors for falls in this population.Methods: We analyzed the data from two randomized, placebo controlled trials (NET-PD FS1 and FS-TOO) of 413 individuals with early PD over 18 months of follow-up in FS1 and 12 months in FS-TOO. Falls were defined as any report of falls on the UPDRS or the adverse event log. We assessed the frequency of falls overall and by age. The relationship between prespecified fall risk markers and the probability of falling was assessed using logistic and multiple logistic regression. A hurdle Poisson model was used to jointly model the probability of remaining fall-free and the number of falls.Results: During the follow-up period, 23% of participants fell, and 11% were habitual fallers. In a multiple logistic regression model, age, baseline UPDRS Falling score, and baseline PDQ-39 scores were associated with subsequent fall risk (p 0 was associated with the number of falls.Conclusion: Falls are frequent and are associated with impaired quality of life, even in early PD. Current standard rating scales do not sufficiently explain future fall risk in the absence of a prior fall history. New assessment methods for falls and postural instability are required to better evaluate this important problem in clinical trials and clinical practice.

Actigraphic study of tremor before and after treatment with zonisamide in patients with Parkinson's disease - Corrected Proof

2012-04-30

In Parkinson's disease (PD), resting tremor, postural tremor, or both often occur as initial symptoms. Levodopa and anticholinergic drugs have been used to manage tremor in PD. However, zonisamide (ZNS) an anticonvulsant, was reported to have beneficial effects especially for “wearing-off” symptoms in patients with PD . Miwa et al. reported that ZNS significantly suppressed tremor in an experimental rat model of PD. On the basis of these findings, ZNS has been used since 2009 to manage tremor in Japanese patients with PD. We have previously used actigraphy to quantitatively evaluate tremor in patients with PD and essential tremor . An actigraph is a motion-sensing apparatus that can detect three-dimensional motor counts of 0.01 G or more. In this study, we quantitatively evaluated tremor by actigraphy before and after treatment with ZNS in PD patients in order to objectively assess whether ZNS is useful for the management of tremor in PD.

Generalized chorea–ballism in acute non ketotic hyperglycemia: Findings from diffusion-weighted magnetic resonance imaging - Corrected Proof

2012-04-30

Non-ketotic hyperglycemic chorea–ballism (NKHCB) is a rare movement disorder associated with poorly controlled type 2 diabetes. In the majority of cases this rare complication is characterized by a triad: unilateral hemichorea–hemiballism, controlateral striatum hyperintensity on T1-weighted Magnetic Resonance imaging (MRI) and reversal of symptoms after normalization of glycemia .

Long-term 24-h levodopa/carbidopa gel infusion in Parkinson's disease - Corrected Proof

Karin Busk, Dag Nyholm — 2012-04-30

Daytime infusion with levodopa/carbidopa intestinal gel (LCIG, Duodopa®) effectively reduces motor and non-motor symptoms in advanced Parkinson's disease (PD) . Some patients use 24-h infusion to treat severe nighttime disability , but long-term consequences are not known. One case treated with 24-h levodopa infusion in 1990 developed tolerance within a few weeks . Only few cases on 24-h LCIG are have so far been reported in the literature .

New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism - Corrected Proof

2012-04-26

Abstract: Background: A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized.Methods: The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews.Results: In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder.Conclusions: The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease.

Hardware complications in deep brain stimulation: Electrode impedance and loss of clinical benefit - Corrected Proof

Jorge Guridi, Maria C. Rodriguez-Oroz, Manuel Alegre, Jose A. Obeso — 2012-04-23

Abstract: Background: Deep brain stimulation (DBS) is an effective treatment in patients with movement disorders. Successful outcomes are correlated with patient selection, accurate placement of the electrodes in their surgical target and optimal programming of patients. The loss of clinical efficacy after successful treatment may be related to hardware complications.Objectives: We studied the causes of loss of stimulation efficacy in patients with stable antiparkinsonian benefit after DBS.Results: Seven out of 110 (6.3%) patients surgically treated with DBS showed a loss of clinical efficacy, and were included in the study. Five cases had subacute clinical worsening and two sudden deterioration. All of them had an impedance increment (>4000 Ω) with the active contacts. Further reprogramming was attempted in all the cases using the undamaged contacts. However, five patients had incomplete clinical control and were reoperated with an electrode replacement. X-rays provided information in all cases except one showing the disruption or rupture of electrode.Conclusions: It is important to identify this hardware problem in view of the growing number of patients receiving this therapy. A protocol for patients with loss of stimulation efficacy and electrode impedance increment needs to be created in clinical visits in order to detect the failed stimulation mechanism.

The relationship between cerebral vascular disease and parkinsonism: The VADO study - Corrected Proof

2012-04-23

Abstract: Background: The observation of gait abnormalities, parkinsonism and vascular lesions in elderly patients is often reported as vascular parkinsonism (VP). However the status of striatal dopamine transporter (DAT) and the effects of brain vascular lesions on motor features and levodopa responsiveness are poorly defined.Methods: We recorded clinical features, chronic response to levodopa and vascular risk factors in a cross-sectional cohort of consecutive elderly patients with possible Parkinson's disease (PD) or VP recruited in 20 centers in Italy.Results: We included a total of 158 patients. Onset of motor symptoms was asymmetric in 93 (59%) and symmetric in 65 patients (41%). Symmetric motor onset was associated with greater disease severity. Chronic levodopa response was positive in 75 (47.8%) and negative in 82 patients (52.2%). A negative response to levodopa was associated with greater frequency of symmetric onset of motor symptoms, worst disease severity, absence of dyskinesia and greater number of vascular risk factors. Frontal lobe showed largest vascular load. Striatal DAT was normal in 48 (30.4%) and abnormal in 110 (69.6%) patients. Patients with normal DAT binding showed higher vascular load at MRI. Significant predictive factors of worst disease severity and negative response to levodopa were hypertension, vascular lesions in basal ganglia/periventricular regions, and normal DAT uptake.Conclusions: Multiple cerebral vascular lesions modify clinical presentation and severity in patients with parkinsonism and this is underlined by specific risk factors primarily hypertension. Striatal DAT assessment is helpful in identifying patients where therapy benefit is less likely.

GPi and STN deep brain stimulation can suppress dyskinesia in Parkinson's disease - Corrected Proof

2012-04-23

Abstract: Objectives: To compare subthalamic nucleus (STN) to globus pallidus internus (GPi) deep brain stimulation (DBS) for control of motor fluctuations and for potential dyskinesia-suppressing qualities.Methods: We conducted a retrospective database review of all patients who underwent GPi or STN DBS for idiopathic Parkinson's disease. Direct dyskinesia suppression (dDS) was defined as improvement in dyskinesia subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) part IV (items 32–34), despite lack of reduction in dopaminergic medication dosage. We analyzed the data using methods appropriate for a case–control study.Results: A total of 133 patients were evaluated. At the last evaluation Dyskinesia scores and motor fluctuations significantly improved in both the GPi (p < 0.0001) and STN groups (p < 0.0001). The GPi group was more likely than the STN group to experience dDS (odds ratio = 1.95, 95% CI = 0.556, 3.21). However, the association between DBS target and dDS was not statistically significant (Pearson chi-square = 2.286, p = 0.131).Conclusions: The overall clinical outcome of STN and GPi DBS for control of dyskinesia and motor fluctuations was similar. STN and GPi DBS both had some direct dyskinesia suppression effects.

Self perceived weakness in Parkinson's disease - Corrected Proof

Joseph H. Friedman, Ana M. Abrantes — 2012-04-23

Abstract: Background: Parkinson's disease (PD) has been known as “The Shaking Palsy” as well as “Paralysis Agitans”, yet clinically apparent weakness is not a feature of the disorder. Relative weakness, and early muscle fatigue may be demonstrated on testing but frank weakness should not be apparent on routine clinical examination.Aim: To determine the prevalence of self perceived weakness (SPW) and whether this feeling was associated with the sense of fatigue.Methods: We asked 113 consecutive PD patients, who had no demonstrable weakness on routine neurological exam and were able to provide reliable answers, whether they perceived themselves to be weak, and whether they felt fatigued. We did not use a fatigue questionnaire or measure strength. The motor scale of the Unified Parkinson's Disease Rating Scale was also used to evaluate every subject.Results: Self perceived weakness was reported by 43.8%. Self perceived weakness was associated with fatigue but not with bradykinesia, tremor or total motor score (motor severity). SPW is common in PD but affects less than half the studied population. SPW appears to be related to fatigue, a major determinant of quality of life in PD, and therefore is an important symptom to understand.

LRRK2 I2020T mutation is associated with tau pathology - Corrected Proof

2012-04-23

Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal-dominant familial Parkinson's disease (FPD). The variable pathological features of LRRK2-linked FPD include Lewy bodies, degeneration of anterior horn cells associated with axonal spheroids, neurofibrillary tangles (NFTs) and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusion bodies. Furthermore, abnormal hyperphosphorylation of microtubule associated protein tau, in part generated by catalysis of protein kinases, has been reported to be involved in progressive neurodegeneration in a number of diseases, including FPD. Thus, we examined six patients carrying the LRRK2 I2020T mutation, a pathogenic mutation associated with PARK8, and found abnormal tau phosphorylation depositions in the brainstem. Additionally, we found LRRK2 I2020T enhanced tau phosphorylation in cultured cells co-expressing LRRK2-I2020T and 3 or 4-repeated tau. This is the first report describing the relationship between hyperphosphorylation of tau and LRRK2 I2020T.

Control of phonatory onset and offset in Parkinson patients following deep brain stimulation of the subthalamic nucleus and caudal zona incerta - Corrected Proof

2012-04-23

Abstract: Laryngeal hypokinesia is a common symptom in Parkinson's disease (PD) that affects quality of life. Deep brain stimulation (DBS) is well recognized as a complementary method for treatment of motor symptoms in PD but the outcomes on patients' control over phonatory alternation have yet not been clearly elucidated. The present study examined the effect of subthalamic nucleus STN-DBS (n = 8, aged 51–72 yrs; median = 63 yrs) and caudal Zona incerta cZi-DBS (n = 8, aged 49–71 yrs; median = 61 yrs) on control of onset and offset of phonation in connected speech. The patients were evaluated in a preoperatively (Med ON, 1.5 times the ordinary Levodopa dose) and 12 months post-operatively (Med ON, ordinary Levodopa dose). The results provided evidence of a progressive reduction in the ability to manifest alternations between voicing and voiceless states in a reading task. Mean proportion produced with inappropriate voicing increased from 47.6% to 55.3% and from 62.9% to 68.6% of the total duration for the two groups of patients between Pre-op and Post-op, Stim OFF evaluations. The medial and final parts of the fricative were more affected than the initial part, indicating an increased voicing lead into the following vowel. We propose that this reduction in phonatory control is be due to either progression of the disease, an effect of reduced Levodopa dosage or a microlesional effect. Patients' proficiency in alternating between voiced and voiceless states in connected speech remained unaffected by both STN-DBS and cZi-DBS.

Drivers with parkinson's disease: Who participates in research studies? - Corrected Proof

Alexander M. Crizzle, Anita M. Myers, Quincy J. Almeida — 2012-04-23

Abstract: Background: Concern about the effects of Parkinson's disease (PD) on driving competence has precipitated many studies, although most have consisted of small samples. Findings are difficult to interpret and compare as researchers have employed different inclusion/exclusion criteria and rarely provide information on the number of PD patients who are no longer driving, fail to meet other criteria, or refuse to participate.Methods: The present study examined barriers to participation and representativeness of research participants by screening PD patients at a movement disorder research center to develop a profile of patients who were currently driving versus those who had stopped driving, and to ascertain eligibility and willingness to participate in driving research.Results: Over 13 months, 128 PD patients were screened (mean age 69.2 ± 10.1; range 39–90); 62% men; with UPDRS motor scores ranging from 8.5 to 68 (mean 30.3 ± 11.3). Only 66% were still driving, and compared to those who had stopped driving, current drivers were more likely to be men (p < .05), younger (p < .05), experienced less severe motor dysfunction (p < .001) and were less likely to report freezing symptoms (p < .05). Less than half (48%) who were eligible for the study agreed to participate. The primary reasons for refusal was having their driving assessed and fear of being reported to licensing authorities.Conclusions: Recruitment of women and participants from various ethnic, educational and socioeconomic backgrounds are important when considering the generalizability of study findings and are needed to develop fitness to drive guidelines in persons with PD.

‘Corrigendum to “Increased Levels of Endothelial Progenitor Cells in Parkinson's Disease” [Parkinsonism Rel Dis 17 (2011) 651–652]’ - Corrected Proof

Ferruccio Cavanna, Michela Barichella, Erica Cassani, Gianni Pezzoli — 2012-04-23

The authors regret that the names of the authors were inverted prior to publication. The correct authorship is as given: Ferruccio Cavanna, Michela Barichella, Erica Cassani, Gianni Pezzoli.

Phenocopies in families with essential tremor and restless legs syndrome challenge Mendelian laws. Epigenetics might provide answers - Corrected Proof

Alexander Zimprich — 2012-04-20

Abstract: Essential Tremor (ET) and Restless Legs Syndrome (RLS) are both highly heritable neurological disorders. The frequent occurrence of multi-incident families suggests the existence of highly penetrant alleles. However, linkage analyses and positional cloning approaches performed within the last 10 years essentially failed to identify responsible mutations. Several loci were found, but their relevance was questioned given the occurrence of suspected phenocopies in many of those families. Remarkably, in some ET and RLS families with an apparent autosomal dominant mode of transmission, the proportion of affected individuals was higher than the expected 50% and therefore suggests a non-mendelian inheritance in some cases. In fact, there is increasing evidence that epigenetic modifications, which refer to changes in gene expression without changes in DNA sequence, can be transmitted to the next generation. Moreover, epigenetic information can be transferred from one allele of a gene to the other allele of the same gene; if then inherited to the next generation, the offspring consequently presents phenotypic properties related to the untransmitted allele. This phenomenon known as paramutation is well documented in plants and has recently been shown to occur also in mammals. Here, I explore the possibility that it is the epigenetic and not only the genetic state which confers disease risk in families. Inheritance of epigenetic mutations along with paramutational events have the potential to explain the non-mendelian features in the genetics of both diseases.

Construction and validation of the Dynamic Parkinson Gait Scale (DYPAGS) - Corrected Proof

Julien Crémers, Rémy Phan Ba, Valérie Delvaux, Gaëtan Garraux — 2012-04-19

Abstract: The dynamic evaluation of Parkinson's disease (PD)-related episodic gait disturbances in routine is challenging. Therefore, the aim of our study was to assess the reliability/validity of the Dynamic Parkinson Gait Scale (DYPAGS) composed of eight relevant items for the objective quantification of PD gait features: walking forwards/backwards/with dual-task, turning to both sides, imaginary obstacle avoidance with both legs and passing through narrow spaces. The scale was validated on thirty-five patients with mild to severe parkinsonism in their habitual “on-state”. A shorter 6 item-version was designed on the basis of a principal component analysis. No significant floor/ceiling effect was detected. The internal consistency was excellent. The levels of interrater agreement, precision and minimal detectable change were adequate. The criterion-related validity was demonstrated by strong correlations with the DYPAGS scores and those at the gait subscales of the Tinetti Mobility Test and MDS-UPDRS. The construct validity was assessed by moderate-strong correlations with the Freezing of Gait Questionnaire, mobility index of the PD Questionnaire (PDQ-39), disease duration and levodopa equivalent daily doses. Statistical analyses using the coefficient of determination showed that both DYPGAS versions were superior to the other instruments to identify patients with gait disturbances with poorer response to dopaminergic treatment. Full and short DYPAGS are reliable instruments for the quantification of “on” PD-related episodic gait disturbances. The full version is sensitive to detect subtle disturbances in mild parkinsonism. The shorter one is easily administered and reliably quantifies gait disturbances in moderate to severe parkinsonism. We recommend their use for research and clinical practice.

Dystonia in Costello syndrome - Corrected Proof

2012-04-17

Abstract: Background: Costello Syndrome is a rare multiple congenital anomaly disorder caused by de novo heterozygous mutations in the v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) gene. Recent studies seem to support apparent autosomal dominant inheritance and somatic mosaicism and an association with advanced parental age. Abnormal hand posture has been reported as a typical feature of Costello Syndrome but the pathophysiology of this is unclear.Methods: We evaluated and described posture and movement in six consecutive subjects with genetically proven Costello Syndrome, in order to better characterize the phenomenology of the associated postural abnormalities and any related motor abnormalities. We also evaluated motor cortex plasticity by applying Paired Associative Stimulation.Results: All the patients presented the typical postural abnormalities reported in Costello Syndrome, in particular the ulnar deviation of fingers. The latter was reducible and not fixed. In addition, patients exhibited more explicit dystonic features of the face, limbs and trunk and altered sensorimotor plasticity consistent with generalized dystonia.Conclusions: These findings suggest that dystonia may underlie the abnormal postures described in Costello Syndrome patients.

Resting-state brain connectivity in patients with Parkinson's disease and freezing of gait - Corrected Proof

2012-04-17

Abstract: Background: Freezing of gait is a common cause of disability and falls in patients with Parkinson's disease. We studied brain functional connectivity, by means of resting-state functional magnetic resonance imaging, in patients with Parkinson's disease and freezing of gait.Methods: Resting-state functional magnetic resonance imaging at 3 T was collected in 29 patients with Parkinson's disease, of whom 16 presented with freezing of gait as determined by a validated freezing of gait questionnaire, and 15 matched healthy controls. Single-subject and group-level independent component analysis was used to identify the main resting-state networks differing between Parkinson's disease patients with and without freezing of gait. Statistical analysis was performed using BrainVoyager QX.Results: Between-group differences in resting-state networks revealed that patients with freezing of gait exhibit significantly reduced functional connectivity within both “executive-attention” (in the right middle frontal gyrus and in the angular gyrus) and visual networks (in the right occipito-temporal gyrus) [p < 0.05 corrected for multiple comparisons]. Freezing of gait clinical severity was significantly correlated with decreased connectivity within the two networks. Consistent with their “executive-attention” network impairment, patients with freezing of gait scored lower on tests of frontal lobe functions (phonemic verbal fluency: p = 0.005; frontal assessment battery: p < 0.001; ten point clock test: p = 0.04).Conclusions: Our findings suggest that a resting-state functional connectivity disruption of “executive-attention” and visual neural networks may be associated with the development of freezing of gait in patients with Parkinson's disease.

The validity and reliability of the Italian Olfactory Identification Test (IOIT) in healthy subjects and in Parkinson's disease patients - Corrected Proof

2012-04-17

Abstract: Background: Olfactory function can be rapidly evaluated by means of standardized olfactory tests. Multiple-choice smell identification tests can be conditioned by cultural background. To investigate a new tool for detecting olfactory deficit in Italian subjects we developed a multiple-choice identification test prepared with odorants belonging to the Italian culture.Methods: The Italian Olfactory Identification Test (IOIT) was developed with 33 microencapsulated odorants with intensity of odors and headspace Gas Chromatography being tested. Test-retest reliability of the IOIT was evaluated. The IOIT was administered to 511 controls and 133 Parkinson's patients.Results: In healthy subjects the number of IOIT errors increased with age for both females (p < 0.0001) and males (p < 0.0001), while in the Parkinson's disease group the number of IOIT errors was significantly greater where compared to healthy subjects (p < 0.0001 in all age groups). The reference limits applied to all age groups revealed an IOIT sensitivity of 93% and a specificity of 99%. The test-retest reliability was excellent.Conclusion: The IOIT is highly reliable, disposable, easy to administer, not fragile, and has a long shelf-life. All these features make the IOIT suitable for clinical use as well as for population screening and to discriminate Parkinson's patients from healthy subjects.

Attention and visual dysfunction in Parkinson's disease - Corrected Proof

Hugo Botha, Jonathan Carr — 2012-04-13

Abstract: Visual processing extends from the retinal level to the ventral temporal lobe, and is modified by top-down and bottom-up processing. Complex visual hallucinations (VH) are commonly a feature of disorders which affect temporal lobe structures, frequently in association with impairment of ascending monoaminergic pathways. When Parkinson's disease (PD) is associated with VH, pathological changes characteristically affect the temporal lobes, a finding which is recapitulated by imaging findings. However, a major association of VH is with cognitive decline, and this is typically linked to deficits in attention and working memory, both of which are modulated by dopamine. Similarly, dopamine plays a crucial role in the function of prefrontal cortex, in addition to controlling access to consciousness via gating mechanisms that are dependent on the basal ganglia.

The DJ-1 concentration in cerebrospinal fluid does not differentiate among parkinsonian syndromes - Corrected Proof

2012-04-13

DJ-1 is a ubiquitously expressed protein involved in cellular oxidative stress rescue mechanisms. It has been shown to inhibit alphasynuclein aggregation and mutations in the DJ-1 gene cause autosomal recessive early-onset Parkinson's disease (PD) . Because of this relationship between PD and DJ-1, the DJ-1 concentration in the cerebrospinal fluid (CSF) has been proposed as a potential biomarker for PD and previous studies have demonstrated decreased CSF DJ-1 levels in patients with PD and multiple system atrophy (MSA) compared to controls .

Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson's disease occurring with Type 2 diabetes in a Taiwanese population cohort - Corrected Proof

2012-04-12

Abstract: Objectives: Type 2 diabetes (T2DM) may increase the risk of Parkinson's disease (PD). We evaluated the role of oral anti-hyperglycemic agents (OAA) in any diabetes–PD linkage.Methods: From the Taiwan National Health Insurance database on 01-01-2000, a representative cohort of 800,000 was obtained between 1996-01-01 and 2007-12-31. Those ≥20 years were classified by presence (n = 64,166) or absence (n = 698,587) of T2DM, and whether any OAA (n = 41,003) or not (n = 23,163) was used. Those with T2DM were matched with those diabetes-free by birth-date and gender for the comparison of PD incidence. We considered those ≥50 years and matched PD-free diabetes patients with and without OAAs by age, gender, locality, health service, Charlson comorbidity index and T2DM diagnosis-date to avoid ‘immortal time bias’. PD incidence densities (PID, per 10,000 person-years) and hazard ratios (HRs) were calculated.Results: HRs (95% confidence interval, CI), related to diabetes-free, were 2.18 (1.27–3.73) and 1.30 (0.77–2.19) for T2DM without and with OAAs. For sulfonylurea alone, PID (95% CI) increased from 58.3 (46.6–70.1) to 83.2 (68.6–97.7), with similar findings by gender, but little difference if metformin was used. The metformin-alone HR (95% CI) was 0.95 (0.53–1.71), sulfonylurea-alone 1.57 (1.15–2.13), and combined therapy 0.78 (0.61–1.01) and these differences persisted when incident PD was excluded for 4 years after T2DM diagnosis. The use of metformin first, in those without insulin, provided an HR of 0.40 (0.17–0.94).Conclusions: Incident PD risk in T2DM increases 2.2-fold. Sulfonylureas further increase risk by 57%, which is avoided by combination with metformin.

Cortical myoclonus in childhood and juvenile onset Huntington's disease - Corrected Proof

2012-04-12

Abstract: Objective: Huntington's disease (HD) appearing before the age of 20 years gives rise to a distinct phenotype with respect to the classical adult-onset disease. Here we describe three patients with childhood or juvenile HD onset presenting with action myoclonus.Methods: We performed jerk-locked back-averaging (JLBA), EEG-EMG coherence and phase analysis, long-loop reflexes (LLRs) and somatosensory evoked potentials (SSEPs). In one patient, we also performed transcranial magnetic stimulation (TMS) using single and paired pulses.Results: In all patients, the EMG features revealed movement activated quasi-rhythmic repetitive jerks; the JLBA and EEG-EMG spectral and coherence profiles indicated a cortical generator of the myoclonus. All patients had enhanced LLRs during muscle contraction, while none showed giant SSEPs. The evaluation of intracortical inhibition by means of TMS revealed reduced inhibition at short and long interstimulus intervals.Conclusions: The rhythmic course of the action myoclonus and the characteristics of the LLRs suggest that myoclonus is due to a reverberant circuit involving the motor cortex, possibly because of an imbalance between excitatory and inhibitory cortical neuronal systems.Significance: Our findings suggest a similar cortical dysfunction in childhood and juvenile onset HD, which probably results from a specific circuitry impairment.

Older participants are frequently excluded from Parkinson's disease research - Corrected Proof

P.R. Fitzsimmons, S. Blayney, S. Mina-Corkill, G.O. Scott — 2012-04-11

Abstract: Background: The exclusion of older participants from clinical research is common and limits the generalisation of research findings. We aimed to assess the current potential for older patients to participate in Parkinson's disease (PD) research.Method: We performed a systematic analysis of data extracted from the World Health Organization Clinical Trials Registry Platform regarding 206 actively recruiting PD research studies. Data regarding study variables and exclusion on the grounds of an upper age limit was extracted from each registry entry and subsequently used for statistical analysis.Results: Exclusion by arbitrary upper age limit is common, with 101 (49%) of studies excluding participants by age and with a mean upper age limit for exclusion of 79.3 years (range 64–95 years). Exclusion by age was significantly more common in studies with an estimated enrolment of fewer than 100 participants; OR 1.92 (95%CI 1.13–3.42) P = 0.018. Rates of exclusion by age were not significantly influenced by study subject, study location, source of funding, study duration or number of centres.Conclusion: Exclusion of participants from PD research on the basis of an upper age limit is common and particularly problematic in smaller studies. The exclusion of older participants seriously compromises the generalisation of findings from PD research to the large numbers of elderly PD patients seen in clinical practice.

Paroxysmal kinesigenic dyskinesia: Cortical or non-cortical origin - Corrected Proof

2012-04-05

Abstract: Paroxysmal kinesigenic dyskinesia (PKD) is characterized by involuntary dystonia and/or chorea triggered by a sudden movement. Cases are usually familial with an autosomal dominant inheritance. Hypotheses regarding the pathogenesis of PKD focus on the controversy whether PKD has a cortical or non-cortical origin. A combined familial trait of PKD and benign familial infantile seizures has been reported as the infantile convulsions and paroxysmal choreoathetosis (ICCA) syndrome. Here, we report a family diagnosed with ICCA syndrome with an Arg217STOP mutation. The index patient showed interictal EEG focal changes compatible with paroxysmal dystonic movements of his contralateral leg. This might support cortical involvement in PKD.

IgM-monoclonal gammopathy neuropathy and tremor: A first epidemiologic case control study - Corrected Proof

Matthew C. Ahlskog, Neeraj Kumar, Michelle L. Mauermann, Christopher J. Klein — 2012-04-04

Abstract: Introduction: Small case series suggest tremor occurs frequently in IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS) neuropathy. Epidemiologic study to confirm this association is lacking. Whether the neuropathy or another remote IgM-effect is causal remains unsettled.Materials and methods: An IgM-MGUS neuropathy case cohort (n=207) was compared to age, gender, and neuropathy impairment score (NIS) matched, other-cause neuropathy controls (n=414). Tremor details were extracted from structured neurologic evaluation. All patients underwent nerve conductions.Results: Tremor occurrence was significantly higher in IgM-MGUS case cohort (29%) than in control cohort (9.2%) (p=0.001). In IgM-MGUS cases, tremor was associated with worse NIS (p=0.025) and demyelinating nerve conductions (p=0.020), but 11 of 60 (18%) IgM-MGUS cases with tremor had axonal neuropathy. In other-cause neuropathy controls, tremor was associated with axonal nerve conductions (p=0.03) but not with NIS severity (p=0.57). Tremor occurrence associated with older age in controls, (p=0.004) but not in IgM-MGUS cases (p=0.272). Most IgM-MGUS tremor cases (49/60) had a postural-kinetic tremor, 8 had rest tremor, 3 had mixed rest-action. Alternative causes of tremor was identified in 42% of IgM-MGUS cases, the most common type is inherited essential tremor 6/60 (p=0.04).Conclusions: This first epidemiologic case-control study validates association between IgM-MGUS neuropathy and tremor. Among IgM-MGUS neuropathy cases, severity as well as type of neuropathy (demyelinating over axonal) correlated with tremor occurrence. IgM-MGUS paraproteinemia may increase tremor expression in persons recognized with common other risk factors for tremor.

Association between PLA2G6 gene polymorphisms and Parkinson's disease in the Chinese Han population - Corrected Proof

2012-03-29

Abstract: The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2, and has been suggested as the causative gene for autosomal recessive dystonia-parkinsonism. We conducted a case–control study using 531 mainland Chinese Parkinson's disease (PD) patients and 561 healthy controls, and genotyped 4 tag single nucleotide polymorphisms (SNPs) of the PLA2G6 gene: rs4375, rs2267369, rs132985, and rs2284063. Logistic regression analysis revealed no difference in genotype or allele frequencies for any of the SNPs between the sporadic PD group and control group. Similarly, comparison of SNPs in patients with either early-onset (EOPD, ≤50 years) or late-onset (>50 years) PD revealed no statistical differences from controls. We detected no significant association of the 4 SNPs with PD at the genotypic level, after adjustment for age. The rs132985 genotype frequency showed a difference in male patients but not in female patients, but the P value did not survive Bonferroni correction (Pcorr = 0.068). We found that the rs132985 A–rs2284063 C haplotype is marginally associated with increased risk of developing PD (P = 0.048) after 10,000 permutations. These findings suggest that PLA2G6 is not a susceptibility gene for PD in our population. However, a broader examination and a replication of this study in other populations are needed.

Nigro-striatal involvement in primary progressive freezing gait: Insights into a heterogeneous pathogenesis - Corrected Proof

2012-03-29

Abstract: Primary progressive freezing gait (PPFG) is a clinical syndrome underlain by diverse neurodegenerative diseases and characterized by early occurrence of gait freezing. Either degeneration or integrity of the nigrostriatal terminals have been found by SPECT and PET studies. In this retrospective study, we evaluated 123I-FP-CIT SPECT findings in a consecutive series of 13 PPFG patients with detailed clinical evaluation over time (mean follow-up duration: 3.1 ± 1.2 years). In all patients, 123I-FP-CIT SPECT has been performed at the time of first clinical evaluation (1.7 ± 1.4 years after disease onset) and was compared with data from 23 age- and sex-matched healthy subjects. PPFG patients were categorized as having abnormal (n = 8) or normal (n = 5) SPECT. At disease onset, PPFG with abnormal SPECT had more frequent hypophonia, higher UPDRS-III scores and partial levodopa responsiveness. By contrast, PPFG with normal SPECT had more frequent bilateral plantar responses and no response to levodopa. At latest follow-up, initial diagnosis in the abnormal SPECT group was revised (n = 5) to progressive supranuclear palsy (n = 4) and pure akinesia with gait freezing (n = 1). Among the five patients with normal SPECT, follow-up evaluation disclosed corticobasal syndrome (n = 2) and primary lateral sclerosis (n = 1). Dopamine transporter imaging can capture the clinical heterogeneity of PPFG and might have a value to predict possible disease progression.

Deep brain stimulation in disabling involuntary vocalization associated with Huntington's disease - Corrected Proof

Pedro J. Garcia-Ruiz, Joaquin Ayerbe, Javier del Val, Antonio Herranz — 2012-03-29

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by progressive cognitive impairment, psychiatric symptoms and movement disorders including chorea, dystonia and tics . In addition to these symptoms, the presence of involuntary vocalization is not infrequent in HD patients .

Analysis of LRRK2, SNCA, Parkin, PINK1, and DJ-1 in Zambian patients with Parkinson's disease - Corrected Proof

2012-03-27

Abstract: Recent studies delineate substantial genetic components in Parkinson's disease (PD). However, very few studies were performed in Sub-Saharan African populations. Here, we explore the contribution of known PD-causing genes in patients of indigenous Zambian ancestry. We studied thirty-nine Zambian patients, thirty-eight with PD and one with parkinsonian-pyramidal syndrome (18% familial; average onset age 54.9 ± 12.2 years). In the whole group, all SNCA exons and LRRK2 exons 29 to 48 (encoding for important functional domains) were sequenced. In the familial patients and those with onset <55 years (n = 22) the whole LRRK2 coding region was sequenced (51 exons). In the patients with onset <50 years (n = 12), all parkin, PINK1, and DJ-1 exons were sequenced, and dosage analysis of parkin, PINK1, DJ-1, LRRK2, and SNCA was performed. Dosage analysis was also performed in the majority of the late-onset patients.The LRRK2 p.Gly2019Ser mutation was not detected. A novel LRRK2 missense variant (p.Ala1464Gly) of possible pathogenic role was found in one case. Two heterozygous, likely disease-causing deletions of parkin (exon 2 and exon 4) were detected in an early-onset case. Pathogenic mutations were not detected in SNCA, PINK1, or DJ-1. We also report variability at several single nucleotide polymorphisms in the above-mentioned genes.This is the first molecular genetic study in Zambian PD patients, and the first comprehensive analysis of the LRRK2 and SNCA genes in a Sub-Saharan population. Common disease-causing mutations were not detected, suggesting that further investigations in PD patients from these populations might unravel the role of additional, still unknown genes.

Ameliorating effect of low frequency repetitive transcranial magnetic stimulation over the premotor cortex in a case of possible painless legs and moving toes syndrome - Corrected Proof

Ji-Young Kim, Han-Joon Kim, Kyung-Il Park — 2012-03-26

Moving toes syndrome is a rare illness which is characterized by involuntary movement in unilateral or bilateral distal lower extremities mainly on toes, whether accompanied by pain or not . Painless legs and moving toes syndrome (PoLMT) is a rarer disorder than painful legs and moving toes syndrome (PLMT), the pathophysiology of which has been poorly understood and is not clearly distinguishable from PLMT .