An accelerometry-based study of lower and upper limb tremor in Parkinson's disease.

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.

An evaluation of the impact of MAPT, SNCA and APOE on the burden of Alzheimer's and Lewy body pathology.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Glucocerebrosidase mutations in diffuse Lewy body disease.

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.

Multi-modal hallucinations and cognitive function in Parkinson's disease.

BACKGROUND/AIMS: 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. METHODS: 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. RESULTS: Participants with hallucinations performed more poorly on select neuropsychological measures and exhibited more mood symptoms. There were no differences between VHonly and VHplus groups. CONCLUSIONS: PD patients with multi-modal hallucinations are not at greater risk for neuropsychological impairment than those with single-modal hallucinations.

GCH1 expression in human cerebellum from healthy individuals is not gender dependent.

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.

Objective tremor registration during DBS surgery for essential tremor.

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.

FGF20 and Parkinson's disease: no evidence of association or pathogenicity via alpha-synuclein expression.

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.

Glucosidase-beta variations and Lewy body disorders.

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.

Anterocollis: clinical features and treatment options.

BACKGROUND: 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. MATERIAL/METHODS: 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. RESULTS: 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. CONCLUSIONS: The demographic and phenotypic features and treatment outcomes of AC in our cohort were somewhat different from other types of CD.

Is the G2019S LRRK2 mutation common in all southern European populations?

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.

A questionnaire-based (UM-PDHQ) study of hallucinations in Parkinson's disease.

BACKGROUND: Hallucinations occur in 20-40% of PD patients and have been associated with unfavorable clinical outcomes (i.e., nursing home placement, increased mortality). Hallucinations, like other non-motor features of PD, are not well recognized in routine primary/secondary clinical practice. So far, there has been no instrument for uniform characterization of hallucinations in PD. To this end, we developed the University of Miami Parkinson's disease Hallucinations Questionnaire (UM-PDHQ) that allows comprehensive assessment of hallucinations in clinical or research settings. METHODS: The UM-PDHQ is composed of 6 quantitative and 14 qualitative items. For our study PD patients of all ages and in all stages of the disease were recruited over an 18-month period. The UPDRS, MMSE, and Beck Depression and Anxiety Inventories were used for comparisons. RESULTS AND DISCUSSION: Seventy consecutive PD patients were included in the analyses. Thirty-one (44.3%) were classified as hallucinators and 39 as non-hallucinators. No significant group differences were observed in terms of demographics, disease characteristics, stage, education, depressive/anxiety scores or cognitive functioning (MMSE) between hallucinators and non-hallucinators. Single mode hallucinations were reported in 20/31 (visual/14, auditory/4, olfactory/2) whereas multiple modalities were reported in 11/31 patients. The most common hallucinatory experience was a whole person followed by small animals, insects and reptiles. CONCLUSION: Using the UM-PDHQ, we were able to define the key characteristics of hallucinations in PD in our cohort. Future directions include the validation of the quantitative part of the questionnaire than will serve as a rating scale for severity of hallucinations.

Cardiac denervation and dysautonomia in Parkinson's disease: a review of screening techniques.

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.

Peripheral nerve damage associated with administration of taxanes in patients with cancer.

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.

Frontotemporal and striatal SPECT abnormalities in myoclonus-dystonia: phenotypic and pathogenetic considerations.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Beyond Parkinson disease: amyotrophic lateral sclerosis and the axon guidance pathway.

BACKGROUND: We recently described a genomic pathway approach to study complex diseases. We demonstrated that models constructed using single nucleotide polymorphisms (SNPs) within axon guidance pathway genes were highly predictive of Parkinson disease (PD) susceptibility, survival free of PD, and age at onset of PD within two independent whole-genome association datasets. We also demonstrated that several axon guidance pathway genes represented by SNPs within our final models were differentially expressed in PD. METHODOLOGY/PRINCIPAL FINDINGS: Here we employed our genomic pathway approach to analyze data from a whole-genome association dataset of amyotrophic lateral sclerosis (ALS); and demonstrated that models constructed using SNPs within axon guidance pathway genes were highly predictive of ALS susceptibility (odds ratio = 1739.73, p = 2.92x10(-60)), survival free of ALS (hazards ratio = 149.80, p = 1.25x10(-74)), and age at onset of ALS (R(2) = 0.86, p = 5.96x10(-66)). We also extended our analyses of a whole-genome association dataset of PD, which shared 320,202 genomic SNPs in common with the whole-genome association dataset of ALS. We compared for ALS and PD the genes represented by SNPs in the final models for susceptibility, survival free of disease, and age at onset of disease and noted that 52.2%, 37.8%, and 34.9% of the genes were shared respectively. CONCLUSIONS/SIGNIFICANCE: Our findings for the axon guidance pathway and ALS have prior biological plausibility, overlap partially with PD, and may provide important insight into the causes of these and related neurodegenerative disorders.