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ABSTRACT: Over the past two decades, several studies have aimed to quantify the kinetic properties of tremor with primary focus on the upper limbs. However, there is a lack of investigation into the properties of tremor in the lower limbs. The objective of this preliminary study was to investigate the properties of oscillatory movement, at rest and in posture, in both the upper and lower limbs of Parkinson's disease (PD) patients with clinically undetectable to modest rest/postural tremor and healthy controls. PD patients (N=16) and controls (N=8) were examined clinically by a movement disorders specialist and oscillatory movements in all four extremities were evaluated using a portable biaxial accelerometer. While tremor intensity and frequency did not differ between groups, the intraindividual variability of rest and postural tremor frequency in the dexterity-dominant lower limb was lower in people living with PD than in healthy adults. Additionally, rest tremor frequency was discrepant between upper and lower limbs in PD. Our work introduces the possibility that minute variations in lower limb movements, which are imperceptible upon expert clinical exam, can be used to differentiate a diseased sample from a healthy one. These preliminary findings suggest that additional work using objective tremor measurement may improve our understanding of lower limb motor dysfunction in PD and lead to the refinement of current, and the development of new, metrics to enhance early diagnosis, differential diagnosis, and symptom quantification.
Journal of Clinical Neuroscience 04/2013; · 1.25 Impact Factor
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Christian Wider,
Owen A Ross,
Kenya Nishioka,
Michael G Heckman,
Carles Vilariño-Güell,
Barbara Jasinska-Myga,
Nilufer Erketin-Taner,
Rosa Rademakers,
Neill R Graff-Radford,
Deborah C Mash, Spiridon Papapetropoulos,
Ranjan Duara,
Hirotake Uchikado,
Zbigniew K Wszolek,
Matthew J Farrer,
Dennis W Dickson
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ABSTRACT: The study investigates the effects of genetic factors on the pathology of Alzheimer's disease (AD) and Lewy body (LB) diseases, including Parkinson's disease and dementia with Lewy bodies.
A multicentre autopsy series (762 brain samples) with AD, LB or vascular pathology was examined. The effects of the tau gene (MAPT) H1 haplotype, the H1 specific SNP rs242557, APOE and the α-synuclein gene (SNCA) 3'UTR SNP rs356165 on the burden of AD and LB pathology were assessed. Neurofibrillary tangles (NFTs) were counted in four brain regions, senile plaques in five and LBs in four. Braak NFT stage, brain weight and presence of vascular pathology were also documented.
MAPT H1 associated with lower counts of NFTs in the middle frontal (p<0.001) and inferior parietal (p=0.005) cortices, and also with lower counts of senile plaques in the motor cortex (p=0.001). Associations of MAPT H1 with increased LB counts in the middle frontal cortex (p=0.011) and inferior parietal cortex (p=0.033) were observed but were not significant after multiple testing adjustment. The APOE ε4 allele was strongly associated with overall Alzheimer type pathology (all p≤0.001). SNCA rs356165 and the MAPT H1 specific SNP rs242557 did not associate with AD or LB pathology.
This study shows for the first time that MAPT H1 is associated with reduced Alzheimer type pathology which could have important implications for the understanding of disease mechanisms and their genetic determinants.
Journal of neurology, neurosurgery, and psychiatry 04/2012; 83(4):424-9. · 4.87 Impact Factor
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Kenya Nishioka,
Owen A Ross,
Carles Vilariño-Güell,
Stephanie A Cobb,
Jennifer M Kachergus,
David M A Mann,
Julie Snowden,
Anna M T Richardson,
David Neary,
Christopher A Robinson,
Alex Rajput, Spiridon Papapetropoulos,
Deborah C Mash,
Rajesh Pahwa,
Kelly E Lyons,
Zbigniew K Wszolek,
Dennis W Dickson,
Matthew J Farrer
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ABSTRACT: Clinicogenetic and pathological studies have shown that mutations of the glucocerebrosidase gene (GBA) are a risk factor for Parkinson's disease and Lewy body disorders. In the present study, we have identified GBA mutations in 6.8% (4/59) of cases with a pathological diagnosis of diffuse Lewy body disease. Taken with previous studies, it appears that GBA mutations are associated with a more diffuse pattern of Lewy body distribution involving the cerebral cortex than the brainstem/limbic distribution observed in typical Parkinson's disease.
Parkinsonism & Related Disorders 10/2010; 17(1):55-7. · 3.80 Impact Factor
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ABSTRACT: Hallucinations have been linked to a constellation of cognitive deficits in Parkinson's disease (PD), but it is not known whether multi-modal hallucinations are associated with greater neuropsychological dysfunction.
152 idiopathic PD patients were categorized based on the presence or absence of hallucinations and then were further subdivided into visual-only (VHonly; n = 35) or multi-modal (VHplus; n = 12) hallucination groups. All participants underwent detailed neuropsychological assessment.
Participants with hallucinations performed more poorly on select neuropsychological measures and exhibited more mood symptoms. There were no differences between VHonly and VHplus groups.
PD patients with multi-modal hallucinations are not at greater risk for neuropsychological impairment than those with single-modal hallucinations.
Dementia and Geriatric Cognitive Disorders 01/2010; 30(1):51-6. · 2.14 Impact Factor
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Christian Wider,
Sarah Lincoln,
Justus C Dachsel,
Gregory Kapatos,
Michael G Heckman,
Nancy N Diehl, Spiridon Papapetropoulos,
Deborah Mash,
Alex Rajput,
Ali H Rajput,
Dennis W Dickson,
Zbigniew K Wszolek,
Matthew J Farrer
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ABSTRACT: Dopa-responsive dystonia (DRD) is a familial childhood-onset disease characterized by fluctuating dystonia, associated with tremor and parkinsonism in some patients. In most families the disease displays autosomal dominant inheritance due to mutations in the GTP cyclohydrolase 1 gene (GCH1). Penetrance and symptom severity display strong female predominance for which gender-specific GCH1 expression has been hypothesized. In this study, GCH1 mRNA expression was measured in cerebellar tissue from 66 healthy human subjects (30 women), and in cerebellar and nigral tissue from eight individuals. No significant difference was found between men and women with small effect sizes observed. Although the correlation between cerebellar and nigral GCH1 expression remains to be further examined, this exploratory study does not support gender-specific GCH1 expression being the basis for the skewed gender distribution observed in DRD patients.
Neuroscience Letters 07/2009; 462(1):73-5. · 2.11 Impact Factor
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ABSTRACT: Essential Tremor (ET) is characterized by a 4-12-Hz postural and kinetic tremor, most commonly affecting the upper limbs. Deep brain stimulation (DBS) of the thalamus (Vim) has been found to be highly effective in severe/refractory forms of ET. Intra-operative assessment of tremor is performed using clinical methods based on patient and physician perception of tremor intensity. We present for the first time the case of a patient whose tremor was objectively monitored/quantified pre- and intra-operatively using device-based tremor registration to supplement clinical measures. We present the case of a 76-year-old right-handed woman that received unilateral (left-sided) DBS of the ventrointermediate (Vim) nucleus of thalamus (Vim) for medically refractory ET. Tremor was monitored with an accelerometer-based Tremor Pen, which is part of a simple portable device (CATSYS 2000 System, Danish Product Development Ltd., DK, www.catsys.dk). The patient was asked to perform tasks for tremor evaluation before and during thalamic DBS. Tremor quantification revealed a significant improvement (34.7-fold) in the contralateral (right) limb following macro-stimulation. No significant improvement was registered in the ipsilateral (non-operated) side. Simple electronic tremor registration methods during DBS of the Vim nucleus of the thalamus may supplement the existing methodology that is solely based on subjective measures derived from clinical observations.
Clinical neurology and neurosurgery 02/2009; 111(4):376-9. · 1.30 Impact Factor
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Christian Wider,
Justus C Dachsel,
Alexandra I Soto,
Michael G Heckman,
Nancy N Diehl,
Mei Yue,
Sarah Lincoln,
Jan O Aasly,
Kristoffer Haugarvoll,
John Q Trojanowski, [......],
Deborah Mash,
Alex Rajput,
Ali H Rajput,
J Mark Gibson,
Timothy Lynch,
Dennis W Dickson,
Ryan J Uitti,
Zbigniew K Wszolek,
Matthew J Farrer,
Owen A Ross
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ABSTRACT: Genetic variation in fibroblast growth factor 20 (FGF20) has been associated with risk of Parkinson's disease (PD). Functional evidence suggested the T allele of one SNP, rs12720208 C/T, altered PD risk by increasing FGF20 and alpha-synuclein protein levels. Herein we report our association study of FGF20 and PD risk in four patient-control series (total: 1,262 patients and 1,881 controls), and measurements of FGF20 and alpha-synuclein protein levels in brain samples (nine patients). We found no evidence of association between FGF20 variability and PD risk, and no relationship between the rs12720208 genotype, FGF20 and alpha-synuclein protein levels.
Movement Disorders 02/2009; 24(3):455-9. · 4.51 Impact Factor
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Movement Disorders 11/2008; 24(2):309-11. · 4.51 Impact Factor
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ABSTRACT: Anterocollis (AC) is a form of cervical dystonia (CD) that produces patterned, repetitive muscle contractions that result in neck flexion. It has been mainly described in the context of parkinsonian movement disorders including Parkinson's disease and multiple system atrophy.
We performed a review of consecutive AC patients seen in our Movement Disorders Clinic over a 15-year period. The diagnosis of AC was based on degree of abnormal neck anteroflexion.
Out of 399 CD patients 27 (6.8%) had features of AC. AC was more prevalent in women (67.3%). It was associated with neuroleptic exposure, PD and a family history of movement/neurological disorder. No definite cases with MSA and AC were described in our cohort. Botulinum toxin injections and tetrabenazine produced clinical improvement.
The demographic and phenotypic features and treatment outcomes of AC in our cohort were somewhat different from other types of CD.
Medical science monitor: international medical journal of experimental and clinical research 10/2008; 14(9):CR427-30. · 1.70 Impact Factor
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ABSTRACT: It has been proposed that there is an increased frequency of glucosidase-beta mutations in Lewy body disorders. Our comprehensive DNA sequencing approach found a small number of glucosidase-beta mutations in 101 neuropathologically defined Lewy body disease cases (3%) compared to 99 healthy post-mortem controls (1%); odds ratio 3.0 (95% CI: 0.3-29, p=0.3). All three affected carriers were classified as diffuse Lewy body disease (n=3/50; 6%). Our study suggests glucosidase-beta variants have a limited role in susceptibility to Lewy body disease in North America.
Parkinsonism & Related Disorders 10/2008; 15(6):414-6. · 3.80 Impact Factor
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ABSTRACT: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, especially the G2019S mutation, have been identified as a common cause of Parkinson's disease in southern European and other Mediterranean populations (Iberians, Ashkenazi Jews and North African Arabs). Owing to the geographic and historic vicinity of Greece with areas of high prevalence of LRRK2 mutations we studied the frequency of the G2019S mutation in a well characterized cohort of familial and sporadic Parkinson's disease patients of Greek origin from mainland Greece. The prevalence of the LRRK2 R1441C mutation and the G2385R Asian polymorphism was also determined. We identified no patients with any of the studied mutations/polymorphisms. Very low prevalence of the LRRK2 G2019S mutation has been reported in other southern European populations. LRRK2 mutations appear to be limited in certain populations and differing ancestry and founder effects may explain the reported variability. Accurate estimations of the frequency and penetrance of different LRRK2 mutations are essential for correct and cost-efficient use of genetic testing and proper genetic counseling of patients with Parkinson's disease.
Journal of Clinical Neuroscience 08/2008; 15(9):1027-30. · 1.25 Impact Factor
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European Neurology 07/2008; 60(2):104-6. · 1.81 Impact Factor
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ABSTRACT: Peripheral neuropathy is a well recognized toxicity of taxanes, usually resulting to dose modification and changes in the treatment plan. Taxanes produce a symmetric, axonal predominantly sensory distal neuropathy with less prominent motor involvement. A "dying back" process starting from distal nerve endings followed by effects on Schwann cells, neuronal body or axonal transport changes and a disturbed cytoplasmatic flow in the affected neurons is the most widely accepted mechanism of taxanes neurotoxicity. The incidence of taxanes-induced peripheral neuropathy is related to causal factors, such as single dose per course and cumulative dose and risk factors including treatment schedule, prior or concomitant administration of platinum compounds or vinca alcaloids, age and pre-existing peripheral neuropathy of other causes. The most reliable method to assess taxanes neurotoxicity is by clinical examination combined with electrophysiological evaluation. There is currently no effective symptomatic treatment for paclitaxel-associated pain, myalgias and arthralgias. Tricyclic antidepressants and anticonvulsants have been used as symptomatic treatment of neurotoxicity with some measure of success. Therefore, new approaches for prophylaxis against taxanes-induced peripheral neuropathy are needed. Several neuroprotective agents including, thiols, neurotrophic factors, and antioxidants hold promise for their ability to prevent neurotoxicity resulting from taxanes exposure. However, further confirmatory trials are warranted on this important clinical topic. This review critically looks at the pathogenesis, incidence, risk factors, diagnosis, characteristics and management of taxanes-induced peripheral neuropathy. We also highlight areas of future research.
Critical Reviews in Oncology/Hematology 07/2008; 66(3):218-28. · 4.41 Impact Factor
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ABSTRACT: Parkinson's disease (PD) has classically been characterized by features of motor dysfunction, but these may manifest only after the nigrostriatal system has incurred significant damage. However, recent evidence suggests that cardiac sympathetic denervation occurs early on in PD. This may trigger a shift in physicians' attention to features of cardiovascular dysautonomia and allow for the evolution of earlier screening techniques. MIBG and PET (6F-DA) scans have demonstrated the functional loss of postganglionic sympathetic cardiac neurons, while immunohistochemical stains have revealed signs of morphological degeneration. Given this information, various screening techniques have been proposed, though most are particular to PD patients with orthostatic hypotension (OH). This is a considerable drawback given that the prevalence of OH in PD patients is estimated to be 41%. We present the argument that a shift in focus is needed; investigators should look for other manners by which to screen patients that are not reliant upon blood pressure. In our point of view, the problem with using blood pressure as a measurement is that it can be affected by many other factors unrelated to cardiac denervation. This may be why many patients with PD cannot be detected using these techniques. In order to make further progress on this front, we believe that investigators should start looking for variables that are more purely dependent upon cardiac denervation. We give one possible example of such a variable in this paper using heart transplant patients as a model.
Parkinsonism & Related Disorders 06/2008; 14(7):524-31. · 3.80 Impact Factor
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Neurology 05/2008; 70(15):1294. · 8.31 Impact Factor
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Movement Disorders 05/2008; 23(5):775. · 4.51 Impact Factor
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ABSTRACT: Acquired chronic hepatocerebral degeneration is a central nervous system disorder secondary to several conditions related to hepatic dysfunction. Clinical features of acquired chronic hepatocerebral degeneration include a hyperkinetic extrapyramidal syndrome, neuropsychiatric symptoms, or both. We present for the first time a pediatric case of acquired chronic hepatocerebral degeneration secondary to endstage biliary disease. The pediatric phenotype of acquired chronic hepatocerebral degeneration is presented, and the differential diagnosis in regard to Wilson's disease and management alternatives are discussed.
Pediatric Neurology 02/2008; 38(1):67-70. · 1.52 Impact Factor
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European Neurology 02/2008; 59(1-2):96-7. · 1.81 Impact Factor
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ABSTRACT: Retrocollis (RC) is a form of cervical dystonia (CD) that produces patterned, repetitive muscle contractions that result in neck extension. We performed a review of consecutive CD patients seen in our Division over a 15-year period. Out of 399 CD patients, 59 (14.8%) had features of RC. Pain was very frequently reported among patients ( approximately 80%). RC was frequently associated with neuroleptic exposure (20.3%) and a history of head/neck trauma (23.7%). Of patients injected with botulinum toxin type A, 24.5% reported excellent, 32.1% moderate, 16.9% mild and 24.5% no response to injections. Oral antidystonic medications had limited contribution to symptom relief.
European Neurology 02/2008; 59(1-2):71-5. · 1.81 Impact Factor
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ABSTRACT: Myoclonus-dystonia (MD) is a rare movement disorder characterized by myoclonic jerks, dystonia and a variety of psychiatric symptoms. Neuroimaging and electrophysiologic studies have not been able to detect any specific central nervous system abnormality. We report for the first time a well-characterized case with MD and abnormal brain perfusion imaging using single photon emission computed tomography (SPECT) with (99m)Tc-ethyl cysteinate dimer (ECD). A review of the literature on the phenotypic and pathogenetic considerations for MD is also presented.
To better define the functional regional central nervous system involvement in MD, we conducted a brain perfusion SPECT with (99m)Tc-ECD in a patient diagnosed with typical disease.
Analysis of the SPECT data revealed significantly reduced regional cerebral blood flow (rCBF) in both temporal lobes (left > right and medial > lateral). Reduced rCBF was also observed in both frontal lobes and the right caudate nucleus.
Our findings of reduced frontotemporal and striatal rCBF in the absence of other neuroimaging and electrophysiologic findings correlate well with the clinical manifestations in our patient and suggest possible functional/metabolic involvement of these areas in the etiopathogenesis of MD.
Neurodegenerative Diseases 02/2008; 5(6):355-8. · 3.06 Impact Factor
