Bimanual Force Coordination in Parkinson’s Disease Patients with Bilateral Subthalamic Deep Brain Stimulation

Objective

Studies of bimanual actions similar to activities of daily living (ADLs) are currently lacking in evaluating fine motor control in Parkinson’s disease patients implanted with bilateral subthalamic deep brain stimulators. We investigated basic time and force characteristics of a bimanual task that resembles performance of ADLs in a group of bilateral subthalamic deep brain stimulation (DBS) patients.

Methods

Patients were evaluated in three different DBS parameter conditions off stimulation, on clinically derived stimulation parameters, and on settings derived from a patient-specific computational model. Model-based parameters were computed as a means to minimize spread of current to non-motor regions of the subthalamic nucleus via Cicerone Deep Brain Stimulation software. Patients were evaluated off parkinsonian medications in each stimulation condition.

Results

The data indicate that DBS parameter state does not affect most aspects of fine motor control in ADL-like tasks; however, features such as increased grip force and grip symmetry varied with the stimulation state. In the absence of DBS parameters, patients exhibited significant grip force asymmetry. Overall UPDRS-III and UPDRS-III scores associated with hand function were lower while patients were experiencing clinically-derived or model-based parameters, as compared to the off-stimulation condition.

Conclusion

While bilateral subthalamic DBS has been shown to alleviate gross motor dysfunction, our results indicate that DBS may not provide the same magnitude of benefit to fine motor coordination.     

Susceptibility-Weighted Imaging Manifestations in the Brain of Wilson’s Disease Patients

Purpose

It is well known that patients with Wilson’s disease (WD) suffer copper metabolism disorder. However, recent studies point to an additional iron metabolism disorder in WD patients. The purpose of our study was to examine susceptibility-weighted imaging (SWI) manifestations of WD in the brains of WD patients.

Methods

A total of 33 patients with WD and 18 normal controls underwent conventional MRI (Magnetic resonance imaging) and SWI. The phase values were measured on SWI-filtered phase images of the bilateral head of the caudate nuclei, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus. Student’s t-tests were used to compare the phase values between WD groups and normal controls.

Results

The mean phase values for the bilateral head of the caudate nuclei, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus were significantly lower than those in the control group (P < 0.001), and bilateral putamen was most strongly affected.

Conclusions

There is paramagnetic mineralization deposition in brain gray nuclei of WD patients and SWI is an effective method to evaluate these structures.     

HNK-1 Carrier Glycoproteins Are Decreased in the Alzheimer’s Disease Brain

The human natural killer-1 (HNK-1), 3-sulfonated glucuronic acid, is a glycoepitope marker of cell adhesion that participates in cell-cell and cell-extracellular matrix interactions and in neurite growth. Very little is known about the regulation of the HNK-1 glycan in neurodegenerative disease, particularly in Alzheimer’s disease (AD). In this study, we investigate changes in the levels of HNK-1 carrier glycoproteins in AD. We demonstrate an overall decrease in HNK-1 immunoreactivity in glycoproteins extracted from the frontal cortex of AD subjects, compared with levels from non-demented controls (NDC). Immunoblotting of ventricular post-mortem and lumbar ante-mortem cerebrospinal fluid with HNK-1 antibodies indicate similar levels of carrier glycoproteins in AD and NDC samples. Decrease in HNK-1 carrier glycoproteins were not paralleled by changes in messenger RNA (mRNA) levels of the enzymes involved in the synthesis of the glycoepitope, β-1,4-galactosyltransferase (β4GalT), glucuronyltransferases GlcAT-P and GlcAT-S, or sulfotransferase HNK-1ST. Over-expression of amyloid precursor protein in Tg2576 transgenic mice and in vitro treatment of SH-SY5Y neuroblastoma cells with the amyloidogenic Aβ42 peptide resulted in a decrease in HNK-1 immunoreactivity levels in brain and cellular extracts, whereas the levels of soluble HNK-1 glycoproteins detected in culture media were not affected by Aβ treatment. HNK-1 levels remain unaffected in the brain extracts of Tg-VLW mice, a model of mutant hyperphosphorylated tau, and in SH-SY5Y cells over-expressing hyperphosphorylated wild-type tau. These results provide evidence that cellular levels of HNK-1 carrier glycoforms are decreased in the brain of AD subjects, probably influenced by the β-amyloid protein.     

Differential Expression of Proteins in Brain Regions of Alzheimer’s Disease Patients

Alzheimer’s disease (AD), a progressive neurodegenerative disorder and the most common form of dementia and cognitive impairment is usually characterized by neuritic amyloid plaques, cerebrovascular amyloidosis and neurofibrillary tangles. In order to find out the pathological protein expression, a quantitative proteome analysis of AD hippocampus, substantia nigra and cortex was performed and the extent of protein expression variation not only in contrast to age-matched controls but also among the understudied regions was analyzed. Expression alterations of 48 proteins were observed in each region along with significant co/contra regulation of malate dehydrogenase, lactate dehydrogenase B chain, aconitate hydratase, protein NipSnap homolog 2, actin cytoplasmic 1, creatine kinase U-type and glyceraldehyde-3-phosphate dehydrogenase. These differentially expressed proteins are mainly involved in energy metabolism, cytoskeleton integration, apoptosis and several other potent cellular/molecular processes. Interaction association network analysis further confirms the close interacting relationship between the co/contra regulated differentially expressed proteins among all the three regions. Elucidation of co/contra regulation of differentially expressed proteins will be helpful to understand disease progression and functional alterations associated with AD.     

Mitochondria with Morphology Characteristic for Alzheimer’s Disease Patients Are Found in the Brain of OXYS Rats

Growing evidence suggests that mitochondrial dysfunction is closely linked to the pathogenesis of sporadic Alzheimer’s disease (AD). One of the key contributors to various aspects of AD pathogenesis, along with metabolic dysfunction, is mitochondrial dynamics, involving balance between fusion and fission, which regulates mitochondrial number and morphology in response to changes in cellular energy demand. Recently, Zhang et al. ((2016) Sci. Rep., 6, 18725) described a previously unknown mitochondrial phenotype manifesting as elongated chain-linked mitochondria termed “mitochondria-on-a-string” (MOAS) in brain tissue from AD patients and mouse models of AD. The authors associated this phenotype with fission arrest, but implications of MOAS formation in AD pathogenesis remain to be understood. Here we analyze the presence and number of MOAS in the brain of OXYS rats simulating key signs of sporadic AD. Using electron microscopy, we found MOAS in OXYS prefrontal cortex neuropil in all stages of AD-like pathology, including mani-festation (5-month-old rats) and progression (12–18-month-old rats). The most pronounced elevation of MOAS content (8–fold) in OXYS rats compared to Wistar controls was found at the preclinical stage (20 days) on the background of decreased numbers of non-MOAS elongated mitochondria. From the age of 20 days through 18 months, the percentage of MOAS-containing neuronal processes increased from 1.7 to 8.3% in Wistar and from 13.9 to 16% in OXYS rats. Our results support the importance of the disruption of mitochondrial dynamics in AD pathogenesis and corroborate the existence of a causal link between impaired mitochondrial dynamics and formation of the distinctive phenotype of “mitochondria-on-a-sting”.     

Neuronal Activity of the Subthalamic Nucleus in Patients with Parkinson’s Disease

The discharge activity of 637 neurons of the human subthalamic nucleus (STN), which were extracellularly recorded during twelve stereotactic surgeries in patients with Parkinson’s disease, has been analyzed. On the basis of the parameters of interspike intervals (ISIs), we have distinguished three major patterns of spontaneous neuronal activity: bursting neurons, regular tonic and irregular tonic neurons. Parametric analysis has enabled us to determine the values of basic parameters in the activity of these three distinguished types of neurons. It has been shown that the representativeness and the activity parameters of three different patterns change in the dorsoventral direction of the STN from the motor to the associative regions. The results will allow researchers to perform targeted search of pathological neuronal activity patterns associated with the motor symptoms of Parkinsonism.     

Comparison of Histological Techniques to Visualize Iron in Paraffin-embedded Brain Tissue of Patients with Alzheimer’s Disease

Better knowledge of the distribution of iron in the brains of Alzheimer’s disease (AD) patients may facilitate the development of an in vivo magnetic resonance (MR) marker for AD and may cast light on the role of this potentially toxic molecule in the pathogenesis of AD. Several histological iron staining techniques have been used in the past but they have not been systematically tested for sensitivity and specificity. This article compares three histochemical techniques and ferritin immunohistochemistry to visualize iron in paraffin-embedded human AD brain tissue. The specificity of the histochemical techniques was tested by staining sections after iron extraction. Iron was demonstrated in the white matter, in layers IV/V of the frontal neocortex, in iron containing plaques, and in microglia. In our hands, these structures were best visualized using the Meguro iron stain, a method that has not been described for iron staining in human brain or AD in particular. Ferritin immunohistochemistry stained microglia and iron containing plaques similar to the Meguro method but was less intense in myelin-associated iron. The Meguro method is most suitable for identifying iron-positive structures in paraffin-embedded human AD brain tissue.     

Identification of miRNA-Target Gene Pairs in the Parietal and Frontal Lobes of the Brain in Patients with Alzheimer’s Disease Using Bioinformatic Analyses

Neurochemical Research - Alzheimer’s disease (AD) is a growing health concern worldwide. MicroRNAs (miRNAs) have been extensively studied in many diseases, including AD. To identify...     

Copper and Zinc in the Serum,Urine, and Hair of Patients with Wilson’s Disease Treated with Penicillamine and Zinc

The purpose of this study was to determine the different levels of copper and zinc in the serum, urine, and scalp hair of patients with Wilson’s disease receiving different, currently accepted methods of treatment to reduce the copper load (penicillamine—group 1, n = 8; zinc—group 2, n = 8; penicillamine+zinc—group 3, n = 8). Blood, urine, and hair samples were collected from the patients. All three treatments resulted in a significant decrease of the serum copper levels. Significantly increased levels of zinc in the serum were detected in the patients in groups 2 and 3 (19.1 and 18.8 μmol/l, respectively; p < 0.05). Copper excretion in the urine significantly increased during its administration to groups 1 and 3 (11.5 and 7.94 μmol/24 h respectively; p < 0.001) due to the effect of penicillamine. The administration of zinc as monotherapy (group 2) or in combination with penicillamine (group 3) led to an increase of its excretion (25.3 and 22.4 μmol/24 h, respectively; p < 0.01). Only an insignificant rise of the copper content in the hair was found in all three groups of patients. The content of zinc in the hair did not differ significantly in any of the groups in comparison with the control group.     

Detection of EBV and HHV6 in the Brain Tissue of Patients with Rasmussen’s Encephalitis

Rasmussen’s encephalitis (RE) is a rare pediatric neurological disorder, and the exact etiology is not clear. Viral infection may be involved in the pathogenesis of RE, but conflicting results have reported. In this study, we evaluated the expression of both Epstein-Barr virus (EBV) and human herpes virus (HHV) 6 antigens in brain sections from 30 patients with RE and 16 control individuals by immunohistochemistry. In the RE group, EBV and HHV6 antigens were detected in 56.7% (17/30) and 50% (15/30) of individuals, respectively. In contrast, no detectable EBV and HHV6 antigen expression was found in brain tissues of the control group. The co-expression of EBV and HHV6 was detected in 20.0% (6/30) of individuals. In particular, a 4-year-old boy had a typical clinical course, including a medical history of viral encephalitis, intractable epilepsy, and hemispheric atrophy. The co-expression of EBV and HHV6 was detected in neurons and astrocytes in the brain tissue, accompanied by a high frequency of CD8⁺ T cells. Our results suggest that EBV and HHV6 infection and the activation of CD8⁺ T cells are involved in the pathogenesis of RE.     

Hair Mineral and Trace Element Content in Children with Down’s Syndrome

Biological Trace Element Research - Chronic exposure to lead causes disruption to energy production mechanisms and tissue damage, in particular through its binding to thiol groups and competition...     

Spectrum of Mutations in the ATP7B Gene in Russian Patients with Wilson’s Disease

Russian Journal of Genetics - Wilson’s disease (WD) is an autosomal recessive disease caused by an excessive accumulation of copper. The molecular genetic etiology of the disease is due to...     

Oxidative Stress in Skin Fibroblasts Cultures of Patients with Huntington’s Disease

Oxidative stress and mitochondrial dysfunction should play a role in the neurodegeneration in Huntington’s disease (HD). The most consistent finding is decreased activity of the mitochondrial complexes II/III and IV of the respiratory chain in the striatum. We assessed enzymatic activities of respiratory chain enzymes and other enzymes involved in oxidative processes in skin fibroblasts cultures of patients with HD. We studied respiratory chain enzyme activities, activities of total, Cu/Zn- and Mn-superoxide-dismutase, glutathione-peroxidase (GPx) and catalase, and coenzyme Q₁₀ (CoQ₁₀) levels in skin fibroblasts cultures from 13 HD patients and 13 age- and sex-matched healthy controls. When compared with controls, HD patients showed significantly lower specific activities for catalase corrected by protein concentrations (P < 0.01). Oxidized, reduced and total CoQ₁₀ levels (both corrected by citrate synthase (CS) and protein concentrations), and activities of total, Cu/Zn- and Mn-superoxide-dismutase, and gluthatione-peroxidase, did not differ significantly between HD-patients and control groups. Values for enzyme activities in the HD group did not correlate with age at onset and of the disease and with the CAG triplet repeats. The primary finding of this study was the decreased activity of catalase in HD patients, suggesting a possible contribution of catalase, but not of other enzymes related with oxidative stress, to the pathogenesis of this disease.     

Imaging Striatal Microglial Activation in Patients with Parkinson’s Disease

This study investigated whether the second-generation translocator protein 18kDa (TSPO) radioligand, [¹⁸F]-FEPPA, could be used in neurodegenerative parkinsonian disorders as a biomarker for detecting neuroinflammation in the striatum. Neuroinflammation has been implicated as a potential mechanism for the progression of Parkinson’s disease (PD). Positron Emission Tomography (PET) radioligand targeting for TSPO allows for the quantification of neuroinflammation in vivo. Based on genotype of the rs6791 polymorphism in the TSPO gene, 16 mixed-affinity binders (MABs) (8 PD and age-matched 8 healthy controls (HCs)), 16 high-affinity binders (HABs) (8 PD and age-matched 8 HCs) and 4 low-affinity binders (LABs) (3 PD and 1 HCs) were identified. Total distribution volume (V_T) values in the striatum were derived from a two-tissue compartment model with arterial plasma as an input function. There was a significant main effect of genotype on [¹⁸F]-FEPPA V_T values in the caudate nucleus (p = 0.001) and putamen (p < 0.001), but no main effect of disease or disease x genotype interaction in either ROI. In the HAB group, the percentage difference between PD and HC was 16% in both caudate nucleus and putamen; in the MAB group, it was -8% and 3%, respectively. While this PET study showed no evidence of increased striatal TSPO expression in PD patients, the current findings provide some insights on the possible interactions between rs6791 polymorphism and neuroinflammation in PD.     

Interleukin-6 Serum Levels in Patients with Parkinson’s Disease

Several lines of evidence suggest that neuroimmune mechanisms may be involved in the neurodegenerative process of Parkinson’s disease (PD). Interleukin-6 (IL-6) is increased in the nigrostriatal region and in the cerebrospinal fluid of patients with PD. IL-6 serum level was evaluated in PD patients. The effects of levodopa treatment and disease severity on IL-6 were also studied. The IL-6 levels were similar between PD patients (treated and not treated) and controls. However, there was a negative correlation of IL-6 levels and the activities of daily living scale (P < 0.05), indicating that patients with more severe disease have higher levels of this cytokine. No correlation involving levodopa treatment and IL-6 serum level was found. The results suggest that only marginal effects of IL-6 occur on the peripheral immune system, and that the role of IL-6 and others neuroimmune factors needs to be well elucidated on PD.     

Dynamics of the Subthalamo-pallidal Complex in Parkinson’s Disease During Deep Brain Stimulation

The dynamics of the subthalamo-pallidal complex in Parkinson’s disease during deep brain stimulation (DBS) were studied using two models, a simple firing-rate model and a population-based model. We extended the simple firing-rate model of the complex formed by the subthalamic nucleus (STN) and the external segment of the Globus Pallidus (GPe) to explore its dynamical regime during DBS. More specifically, the modulation of neuronal activity (i.e., pattern and amplitude) during DBS was studied. A similar approach was used with the population-based model. Simulation results revealed a gradual decrease in bursting activity in STN cells when the DBS frequency increased. In addition, the contribution of the stimulation current type (mono- or biphasic) to the results was also examined. A comparison of the two models indicated that the population-based model was more biologically realistic and more appropriate for exploring DBS mechanisms. Understanding the underlying mechanisms of DBS is a prerequisite for developing new stimulation protocols.     

Atrophic Patterns of the Frontal-Subcortical Circuits in Patients with Mild Cognitive Impairment and Alzheimer’s Disease

Atrophy of the cortical thickness and gray matter volume are regarded as sensitive markers for the early clinical diagnosis of Alzheimer’s disease (AD). This study aimed to investigate differences in atrophy patterns in the frontal-subcortical circuits between MCI and AD, assess whether these differences were essential for the pathologic basis of cognitive impairment. A total of 131 individuals were recruited, including 45 with cognitively normal controls (CN), 46 with MCI, and 40 with AD. FreeSurfer software was used to perform volumetric measurements of the frontal-subcortical circuits from 3.0T magnetic resonance (MR) scans. Data revealed that both MCI and AD subjects had a thinner cortex in the left caudal middle frontal gyrus and the left lateral orbitofrontal gyrus compared with CN individuals. The left lateral orbitofrontal gyrus was also thinner in AD compared with MCI patients. There were no statistically significant differences in the cortical mean curvature among the three groups. Both MCI and AD subjects exhibited smaller bilateral hippocampus volumes compared with CN individuals. The volumes of the bilateral hippocampus and the right putamen were also smaller in AD compared with MCI patients. Logistic regression analyses revealed that the left lateral orbitofrontal gyrus and bilateral hippocampus were risk factors for cognitive impairment. These current results suggest that atrophy was heterogeneous in subregions of the frontal-subcortical circuits in MCI and AD patients. Among these subregions, the reduced thickness of the left lateral orbitofrontal and the smaller volume of the bilateral hippocampus seemed to be markers for predicting cognitive impairment.     

Carpal Tunnel Syndrome in Patients with Tremor Dominant Parkinson’s Disease

Background

Unilateral hand tremor is one of the cardinal symptoms of Parkinson’s disease. Additionally, mechanical traumatic hand movement is one of the risk factors for carpal tunnel syndrome. Our objective in this study was to examine whether repetitive mechanical movement may be related to the development of carpal tunnel syndrome in Parkinson’s disease with unilateral hand tremor using neurophysiological methods.

Methods

The study participants included 33 de novo Parkinson’s disease patients with unilateral hand tremor, and we compared the tremor hand and non-tremor hand within the same patients.

Results

Seven (21.2%) of the 33 patients had carpal tunnel syndrome. All of carpal tunnel syndrome patients showed neurophysiological abnormalities in both the hand without tremor and the hand with tremor. In addition, in patients without carpal tunnel syndrome, the sensory nerve action potential was lower in the hand without tremor than in the hand with tremor, although there were no significant differences.

Conclusions

We concluded that hand tremor in de novo Parkinson’s disease patients was not directly related to the development of carpal tunnel syndrome. In contrast, more frequent use of hand without tremor may induce mechanical loading and may be associated with CTS in the hand without tremor. Early diagnosis of Parkinson’s disease and proper education in hand use may be essential for preventing carpal tunnel syndrome in Parkinson’s disease tremor patients.     

Impaired Retention of Motor Learning of Writing Skills in Patients with Parkinson’s Disease with Freezing of Gait

Background

Patients with Parkinson’s disease (PD) and freezing of gait (FOG) suffer from more impaired motor and cognitive functioning than their non-freezing counterparts. This underlies an even higher need for targeted rehabilitation programs in this group. However, so far it is unclear whether FOG affects the ability for consolidation and generalization of motor learning and thus the efficacy of rehabilitation.

Objective

To investigate the hallmarks of motor learning in people with FOG compared to those without by comparing the effects of an intensive motor learning program to improve handwriting.

Methods

Thirty five patients with PD, including 19 without and 16 with FOG received six weeks of handwriting training consisting of exercises provided on paper and on a touch-sensitive writing tablet. Writing training was based on single- and dual-task writing and was supported by means of visual target zones. To investigate automatization, generalization and retention of learning, writing performance was assessed before and after training in the presence and absence of cues and dual tasking and after a six-week retention period. Writing amplitude was measured as primary outcome measure and variability of writing and dual-task accuracy as secondary outcomes.

Results

Significant learning effects were present on all outcome measures in both groups, both for writing under single- and dual-task conditions. However, the gains in writing amplitude were not retained after a retention period of six weeks without training in the patient group without FOG. Furthermore, patients with FOG were highly dependent on the visual target zones, reflecting reduced generalization of learning in this group.

Conclusions

Although short-term learning effects were present in both groups, generalization and retention of motor learning were specifically impaired in patients with PD and FOG. The results of this study underscore the importance of individualized rehabilitation protocols.