Botulinum toxin treatment of freezing of gait in Parkinson's disease patients as reflected in functional magnetic resonance imaging of leg movement.

BACKGROUND: Freezing of gait (FOG) is a common disabling symptom of (in) Parkinson's disease (PD). The mechanism of FOG is (in) not clearly understood. We investigated the clinical effect and changes of the activity of the sensorimotor system using repeated functional MRI (fMRI) before and after application of botulinum toxin in Parkinson's disease patients with FOG. METHODS: We investigated 20 patients with PD, 10 with FOG and 10 without FOG. PD patients with FOG were treated with intramuscular application of botulinum toxin type A into the tensor fasciae latae muscle bilaterally. The clinical effect of treatment was assessed using FOG questionnaire, "Time up and go" test, UPDRS, Hoehn and Yahr staging, Clinical global impression scale. Activation of the sensorimotor system was studied using BOLD fMRI of the whole brain during repetitive abduction - adduction of each leg interleaved with rest. The clinical (in the FOG group) and imaging (in both groups) examination was repeated after a four-week interval. RESULTS: In the FOG group, the FOG questionnaire has shown a decline of scores after application of botulinum toxin that suggests possible effect of botulinum toxin on freezing of gait. In fMRI results, both groups manifested reduction of the sensorimotor network activated with leg movement, however, the FOG group also showed increased activation in cerebellar vermis and nuclei, in dorsal pons and in medulla after treatment. CONCLUSION: Alleviation of the FOG in PD patients by botulinum toxin seems to be reflected in the functional participation of the cerebellum and its projections as seen by fMRI.

Treatment of camptocormia with continuous subcutaneous infusions of apomorphine: 1-year prospective pilot study.

Camptocormia is defined as a marked dystonic flexion of the trunk in the sagittal plane. Camptocormia responds poorly to botulinum toxin injections, manipulation with dopaminergic treatment, and deep brain stimulation. We designed a prospective pilot study to assess the effect of apomorphine infusions on camptocormia. Five patients were enrolled. All five patients responded well to this treatment. The fact that camptocormia responds so well to apomorphine may be explained by the sustained stimulation of the ventrolateral striatal D1 receptors, alleviating this type of dystonia.

Peripheral neuropathy in Parkinson's disease.

BACKGROUND: Recent studies suggest an increased frequency of peripheral neuropathy (PN) in Parkinson's disease patients (PD) (Toth et al. 2010). The aim of our study is to verify the increased frequency of PN in our group of PD patients compared to an age-matched control group. We sorted patients according to the duration of L-DOPA treatment, L-DOPA dosage, and age below or over 50 years. METHODS AND RESULTS: We conducted electromyography examinations (using conduction studies and needle electromyography) of 49 PD patients with asymptomatic polyneuropathy and 40 controls. Patients without risk factors for PN were included (fasting blood was analyzed to rule out possible causes of PN), as were relatively healthy controls without risk factors for PN. PN was defined using the American Academy of Neurology and Electrodiagnostic Medicine criteria (England et al. 2005). CONCLUSION: The frequency of polyneuropathy was significantly higher in PD patients than in controls (45% versus 2%, p<0.0001). We did not establish a relationship in the PD group according to long-term L-DOPA usage, PD duration, or age. It should be assumed that a neurodegenerative process underlies the involvement of the central and peripheral nervous systems in PD patients.

Deep brain stimulation electrode position impact on parkinsonian non-motor symptoms.

BACKGROUND: In this study we evaluated the impact of location of deep brain stimulation electrode active contact in different parts of the subthalamic nucleus on improvement of non-motor symptoms in patients with Parkinson's disease. METHODS: The subthalamic nucleus was divided into two (dorsolateral/ventromedial) and three (dorsolateral, medial, ventromedial) parts. 37 deep brain stimulation electrodes were divided according to their active contact location. Correlation between change in non-motor symptoms before and one and four months after deep brain stimulation electrode implantation and the location of active contact was made. RESULTS: In dividing the subthalamic nucleus into three parts, no electrode active contact was placed ventromedially, 28 active contacts were located in the medial part and 9 contacts were placed dorsolaterally. After one and four months, no significant difference was found between medial and dorsolateral positions. In the division of the subthalamic nucleus into two parts, 13 contacts were located in the ventromedial part and 24 contacts were placed in the dorsolateral part. After one month, significantly greater improvement in the Non-motor Symptoms Scale for Parkinson's disease (P=0.045) was found on dorsolateral left-sided stimulation, but no significant differences between the ventromedial and dorsolateral positions were found on the right side. CONCLUSION: This study demonstrated the relationship between improvement of non-motor symptoms and the side (hemisphere, left/right) of the deep brain stimulation electrode active contact, rather than its precise location within specific parts of the subthalamic nucleus in patients treated for advanced Parkinson's disease.

Cerebrospinal Fluid Levels of Chromogranin A in Parkinson's Disease and Multiple System Atrophy.

BACKGROUND: Chromogranin A (CgA) and other peptides from the chromogranin-secretogranin family have been recently studied as potential biomarkers of various neurodegenerative diseases, including Parkinson's disease (PD). METHODS: We measured CgA in the cerebrospinal fluid (CSF) of 119 PD patients, 18 multiple system atrophy (MSA) patients, and 31 age-matched controls. We also correlated the values with disease duration and levodopa dose equivalent. RESULTS: In the PD patients, CSF CgA tended to be lower than the control group (median 124.5 vs. 185.2 µg/L; p = 0.057); however, the results did not reach statistical significance. CSF CgA levels in MSA were significantly lower compared to the control group (median 104.4 vs. 185.2; p = 0.014). There was no significant difference in CSF CgA between PD and MSA patients (p = 0.372). There was no association between CSF CgA and disease duration or levodopa dose equivalent in PD or in MSA. CONCLUSIONS: We observed a tendency toward lower CSF CgA levels in both PD and MSA compared to the control group; however, the difference reached statistical significance only in MSA. Based on these results, CgA may have potential as a biomarker in PD and MSA, but further studies on larger numbers of patients are needed to draw conclusions.

Deep Brain Stimulation Effects on Gait Pattern in Advanced Parkinson's Disease Patients.

BACKGROUND: Gait disturbance accompanies many neurodegenerative diseases; it is characteristic for Parkinson's disease (PD). Treatment of advanced PD often includes deep brain stimulation (DBS) of the subthalamic nucleus. Regarding gait, previous studies have reported non-significant or conflicting results, possibly related to methodological limitations. OBJECTIVE: The objective of this prospective study was to assess the effects of DBS on biomechanical parameters of gait in patients with PD. METHODS: Twenty-one patients with advanced PD participated in this prospective study. Gait was examined in all patients using the Zebris FDM-T pressure-sensitive treadmill (Isny, Germany) before DBS implantation and after surgery immediately, further immediately after the start of neurostimulation, and 3 months after neurostimulator activation. We assessed spontaneous gait on a moving treadmill at different speeds. Step length, stance phase of both lower limbs, double-stance phase, and cadence were evaluated. RESULTS: In this study, step length increased, allowing the cadence to decrease. Double-stance phase duration, that is, the most sensitive parameter of gait quality and unsteadiness, was reduced, in gait at a speed of 4.5 km/h and in the narrow-based gaits at 1 km/h (tandem gait), which demonstrates improvement. CONCLUSION: This study suggests positive effects of DBS treatment on gait in PD patients. Improvement was observed in several biomechanical parameters of gait.

Bilateral subthalamic deep brain stimulation initial impact on nonmotor and motor symptoms in Parkinson's disease: An open prospective single institution study.

Numerous studies document significant improvement in motor symptoms in patients with Parkinson's disease (PD) after deep brain stimulation of the subthalamic nucleus (STN-DBS). However, little is known about the initial effects of STN-DBS on nonmotor domains.Our objective was to elucidate the initial effects of STN-DBS on non-motor and motor symptoms in PD patients in a 4-month follow-up.This open prospective study followed 24 patients with PD who underwent STN-DBS. The patients were examined using dedicated rating scales preoperatively and at 1 and 4 months following STN-DBS to determine initial changes in motor and nonmotor symptoms. Patients at month 1 after STN-DBS had significantly reduced the Parkinson's disease Questionnaire scores (P = .018) and Scales for Outcomes in Parkinson's disease - Autonomic scores (P = .002); these scores had increased at Month 4 after DBS-STN. Nonmotor Symptoms Scale for Parkinson's Disease had improved significantly at Month 1 (P < .001); at Month 4, it remained significantly lower than before stimulation (P = .036). There was no significant difference in The Parkinson's Disease Sleep Scaleat Month 1 and significant improvement at Month 4 (P = .026). There were no significant changes in The Female Sexual Function Index or International Index of Erectile Function. Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III scores show significant improvements at Month 1 (P < .001) and at Month 4 (P < .001).STN-DBS in patients with advanced PD clearly improves not only motor symptoms, but also several domains of nonmotor functions, namely sleep, autonomic functions and quality of life quickly following the start of stimulation.

New endemic familial parkinsonism in south Moravia, Czech Republic and its genetical background.

An increased prevalence of familial neurodegenerative parkinsonism or cognitive deterioration was recently found in a small region of southeastern Moravia.The aim of the study was to assess the genetic background of this familial disease.Variants in the ADH1C, EIF4G1, FBXO7, GBA + GBAP1, GIGYF2, HTRA2, LRRK2, MAPT, PRKN, DJ-1, PINK1, PLA2G6, SNCA, UCHL1, VPS35 genes were examined in 12 clinically positive probands of the pedigree in which familial atypical neurodegenerative parkinsonism was identified in previous epidemiological studies. Libraries were sequenced by massive parallel sequencing (MPS) on the Personal Genome Machine (PGM; Ion Torrent). Data were analyzed using Torrent Suite and IonReporter software. All variants were then verified and confirmed by Sanger sequencing.We identified 31 rare heterozygous variants: 11 missense variants, 3 synonymous variants, 8 variants in the UTR region, and 9 intronic variants. Six variants (rs1801334, rs33995883, rs35507033, rs781737269, rs779760087, and rs63750072) were evaluated as pathogenic by at least one in-silico predictor.No single "founder" pathogenic variant associated with parkinsonism has been found in any of the probands from researched pedigree. It may rather be assumed that the familial occurrence of this disease is caused by the combined influence of several "small-effect" genetic variants that accumulate in the population with long-lasting inbreeding behavior.

Freezing of gait is associated with cortical thinning in mesial frontal cortex.

AIMS: The relationship between freezing of gait (FOG) and regional brain atrophy has been intensively investigated, but it is still not clearly understood. The study objective was to test whether grey matter (GM) atrophy contributes to FOG in Parkinson's disease (PD) using a surface-based algorithm. METHODS: We investigated 21 patients with PD, 11 with FOG and 10 without FOG. Both groups were assessed using a FOG questionnaire and Hoehn and Yahr staging. High resolution T1-weighted brain images were acquired for each subject using a 1.5T MRI scanner. A surface-based method implemented in FreeSurfer was used to quantify the GM atrophy. A vertex-wise and region of interest (ROI) comparison of spatially normalized subject data using a general linear model and the Wilcoxon rank sum test were to assess significant group differences. RESULTS: Higher global levels of cortical atrophy were detected in freezers, although this was not statistically significant. The vertex-wise analysis revealed significant local reduction in grey matter thickness in the left supplementary motor area, middle/anterior cingulate cortex, temporal pole and right frontal operculum in freezers at P<0.001, uncorrected. The ROI analysis of average thickness confirmed the regional atrophy in bilateral anterior and posterior cingulate cortices. No significant relative regional cortical atrophy was observed in non-freezers. CONCLUSION: FOG was associated with regional cortical atrophy, especially in mesial frontal and cingulate cortices. Our findings provide additional evidence that the development of FOG in patients with PD is associated with local structural cortical changes.

Familial atypical parkinsonism with rare variant in VPS35 and FBXO7 genes: A case report.

BACKGROUND: A higher prevalence of parkinsonism was recently identified in southeastern Moravia (Czech Republic). Further research confirmed 3 large pedigrees with familial autosomal-dominant parkinsonism spanning 5 generations. METHODS: This case report concerns a patient belonging to one of these 3 pedigrees, in whom motor and oculomotor symptoms were accompanied by frontal-type dementia, who finally developed a clinical phenotype of progressive supranuclear palsy. Molecular genetic examinations were performed due to the positive family history. RESULTS: No previously described causal mutation was found. After filtering against common variants (minor allele frequency (MAF) < 0.01), 2 noncoding and 1 synonymous rare mutation potentially associable with parkinsonism were identified: GIGYF2-GRB10 Interacting GYF Protein 2, PARK11 (c.*2030G > A, rs115669549); VPS35 gene-vacuolar protein sorting 35, PARK17 (c.102 + 33G > A, rs192115886); and FBXO7-F-box only protein 7 gene, PARK15 (c.540A > G, rs41311141). CONCLUSION: As to the changes in the FBXO7 and VPS35 genes (despite phylogenetic conservation in primates), probably neither the FBXO7 nor the VPS35 variants will be direct causal mutations. Both described variants, and possibly the influence of their combination, could increase the risk of the disease.

Clusterin CSF levels in differential diagnosis of neurodegenerative disorders.

INTRODUCTION: Clusterin, a heterodimeric glycoprotein, is thought to be involved in many cellular functions, including cell-cell interaction, cell survival and apoptosis. In the brain, post-mortem analysis has found increased clusterin associated with the pathology of many other neurodegenerative diseases (ND) such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and multiple system atrophy (MSA). In vivo cerebrospinal fluid (CSF) levels of clusterin in ND diseases may reflect differences in the pathology and thus aid in the differential diagnosis. METHODS: CSF levels of clusterin were assessed in 102 patients with clinical manifestations of neurodegenerative diseases (23 patients with PD, 18 with PDD, 15 with DLB, 18 with AD, 16 with PSP, 12 with MSA) and 21 subjects as a control group (CG). RESULTS: Significantly higher CSF clusterin levels were found in PD compared to CG (median 6884 vs. 4484; p=0.012), DLB (median 6884 vs. 4192; p=0.023), MSA (median 6884 vs. 3606; p=0.001) and PSP (median 6884 vs. 4193; p=0.014). Significantly higher CSF clusterin levels were found in PDD compared to CG (median 8617 vs. 4484; p=0.045), DLB (median 8617 vs. 4192; p=0.025) and MSA (median 8617 vs. 3606; p=0.004). CONCLUSION: The results of the presented "feasibility" study support the role of clusterin in PD/PDD pathogenesis. Clusterin CSF levels could serve as a potential marker for PDD and DLB differentiation.

Familial, autosomal-dominant neurodegenerative parkinsonism with cognitive deterioration spanning five generations in a genetically isolated population of south-eastern Moravia, Czech Republic.

BACKGROUND: An epidemiological study conducted over four years revealed increased prevalence of neurodegenerative parkinsonism in a small, isolated region (10 villages, with a combined population of 8664, with approx. 2927 over 50 years of age) of south-eastern Moravia, Czech Republic. The aim of this study was to obtain more detailed information on the medical history of the relatives of individuals with confirmed parkinsonism in an isolated rural population in south-eastern Moravia, Czech Republic. METHODS: We did detailed genealogical research on the families of all inhabitants with confirmed parkinsonism and compiled the pedigrees. These were modified on the basis of information from a consecutive door-to-door survey and local municipal and church registers. RESULTS: In the first stage, three large pedigrees with a familial occurrence of parkinsonism were found; two originated in one of the region's villages. In the second stage, these two pedigrees were combined into one large family tree. CONCLUSIONS: The high prevalence of parkinsonism in the researched area is caused by the familial aggregation of parkinsonism that was found in two large family trees. This is probably the result of the genetic isolation of the regional population due to the very low migration rate of its inhabitants to neighboring regions in the last two centuries.

Tau protein, beta-amyloid1₋42 and clusterin CSF levels in the differential diagnosis of Parkinsonian syndrome with dementia.

BACKGROUND: Parkinson's disease (PD), PD with dementia (PDD) and Lewy body dementia (DLB) are synucleinopathies. PDD and DLB are sometimes considered a transition between PD and Alzheimer dementia (AD). Finding in vivo markers or their combination could help in the differential diagnosis of these neurodegenerative (ND) diseases. OBJECTIVE: The aim of this study was to assess cerebrospinal fluid (CSF) levels of tau protein, betaamyloid1-42 and clusterin and to compare these levels among patients with probable PD, PDD, DLB and AD. METHODS: CSF levels of ND markers were assessed in 96 patients (27 patients with PD, 14 with PDD, 14 with DLB, 17 with AD and 24 subjects as a control group). RESULTS: In all of the groups of patients, beta-amyloid1-42 levels were decreasing in the order PD>PDD>DLB>AD, whereas tau protein and the tau protein/beta-amyloid1-42 index were increasing in the same order (PD