Vladana Markovic

No Association between Brain-Derived Neurotrophic Factor G196A Polymorphism and Clinical Features of Parkinson's Disease

Aims: To investigate association of the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene with clinical features in Serbian patients with Parkinsons disease (PD). Methods: The study comprised 177 consecutive PD patients. A comprehensive set of clinical scales was applied in all patients. The controls (n = 366) were recruited among students. Single nucleotide polymorphisms (SNPs; rs6265) were analyzed using TaqMan assays. Results: PD patients (118 males) were aged 58.9 ± 10.9 years, with a mean age at onset of 49.0 ± 11.2 years. PD patients and controls had a similar distribution of genotypes and allele frequencies. The presence of the Met allele did not influence the clinical characteristics of PD patients (age at onset, family history, gender, disease duration, form of the disease, initial symptoms, cognitive abilities, depression, anxiety, disease severity, severity of motor and prevalence of nonmotor symptoms, and development of motor complications). Conclusion: Overall, the Val66Met polymorphism did not modify the clinical features in PD patients.

Brain structural and functional signatures of impulsive–compulsive behaviours in Parkinson’s disease

This study assessed brain structural and functional alterations in patients with Parkinson’s disease and impulsive–compulsive behaviours (PD-ICB) compared with controls and PD no-ICB cases. Eighty-five PD patients (35 PD-ICB) and 50 controls were recruited. All subjects underwent three-dimensional T1-weighted, diffusion tensor (DT), and resting state functional magnetic resonance imaging (RS fMRI). We assessed cortical thickness with surface-based morphometry, subcortical volumes using FIRST, DT MRI metrics using region of interest and tractography approaches, and RS fMRI using a model free approach. Compared with controls, both PD groups showed a pattern of brain structural alterations in the basal ganglia (more evident in PD no-ICB patients), sensorimotor and associative systems. Compared with PD no-ICB, PD-ICB cases showed left precentral and superior frontal cortical thinning, and motor and extramotor white matter tract damage. Compared with controls, all patients had an increased functional connectivity within the visual network. Additionally, PD no-ICB showed increased functional connectivity of bilateral precentral and postcentral gyri within the sensorimotor network compared with controls and PD-ICB. Severity and duration of PD-ICB modulated the functional connectivity between sensorimotor, visual and cognitive networks. Relative to PD no-ICB, PD-ICB patients were characterised by a more severe involvement of frontal, meso-limbic and motor circuits. These data suggest ICB in PD as the result of a disconnection between sensorimotor, associative and cognitive networks with increasing motor impairment, psychiatric symptoms, and ICB duration. These findings may have important implications in understanding the neural substrates underlying ICB in PD.

Attentional Set-Shifting in Parkinson’s Disease Patients with Freezing of Gait-Acquisition and Discrimination Set Learning Deficits at the Background?

Cognitive loading aggravates the freezing of gait (FoG), which is observed in approximately 50% of patients with Parkinsons disease (PD) in the advanced stages. To investigate whether a specific pattern of executive deficits, that is, attentional set-shifting and/or inhibitory control, are associated with FoG in PD, 30 PD patients with FoG (PD-FoG+) and 36 PD patients without FoG (PD-FoG-) and 22 control healthy subjects were examined with a comprehensive neuropsychological battery. Intra-Extra Dimensional Set shifting Test (IED) and Stop Signal Task (SST), selected from the Cambridge Automated Neuropsychological Battery (CANTAB battery), were administered to analyze set-shifting and motor inhibition, respectively. The IED task was significantly sensitive for differentiating between PD-FoG+ and PD-FoG- groups (p<.01), as well Adenbrooks clock drawing task (p=.033). By contrast, no differences emerged on any aspect of the SST task and other cognitive tasks. The attrition rate during the IED task showed that the problem in the PD-FoG+ group appeared at the pre-ID level, on the discrimination-learning set; the 32% PD-FoG+ subjects did not achieve the ID level of the task in comparison to negligible 4% of the PD-FoG- patients (p=.011). The logistic regression analysis, indicated the higher the IED stage successfully completed, the less likely presence of FoG in PD subjects. These results demonstrate that the complex cognitive-motor interplay might be responsible for FoG in PD and have had real life implication for the patients.

White matter tract alterations in Parkinson's disease patients with punding

OBJECTIVE To assess brain white matter tract alterations in patients with Parkinsons disease and punding (PD-punding) compared with controls and PD cases without any impulsive-compulsive behaviour. METHODS Forty-nine PD patients (21 PD-punding and 28 PD with no impulsive-compulsive behaviours) and 28 controls were consecutively recruited. Clinical, cognitive and psychopathological evaluations were performed. Diffusion tensor MRI metrics of the main white matter tracts were assessed using a tractography approach. RESULTS Compared with controls, both PD groups showed white matter microstructural alterations of the left pedunculopontine tract and splenium of the corpus callosum. PD-punding patients showed a further damage to the right pedunculopontine tract and uncinate fasciculus, genu of the corpus callosum, and left parahippocampal tract relative to controls. When adjusting for depression and/or apathy severity, a greater damage of the genu of the corpus callosum and the left pedunculopontine tract was found in PD-punding compared with patients with no impulsive-compulsive behaviours. CONCLUSIONS PD-punding is associated with a disconnection between midbrain, limbic and white matter tracts projecting to the frontal cortices. These alterations are at least partially independent of their psychopathological changes. Diffusion tensor MRI is a powerful tool for understanding the neural substrates underlying punding in PD.

Role of habenula and amygdala dysfunction in Parkinson disease patients with punding

Objective: To assess whether a functional dysregulation of the habenula and amygdala, as modulators of the reward brain circuit, contributes to Parkinson disease (PD) punding. Methods: Structural and resting-state functional MRI were obtained from 22 patients with PD punding, 30 patients with PD without any impulsive-compulsive behavior (ICB) matched for disease stage and duration, motor impairment, and cognitive status, and 30 healthy controls. Resting-state functional connectivity of the habenula and amygdala bilaterally was assessed using a seed-based approach. Habenula and amygdala volumes and cortical thickness measures were obtained. Results: Compared to both healthy controls and PD cases without any ICB (PD–no ICB), PD-punding patients showed higher functional connectivity of habenula and amygdala with thalamus and striatum bilaterally, and lower connectivity between bilateral habenula and left frontal and precentral cortices. In PD-punding relative to PD–no ICB patients, a lower functional connectivity between right amygdala and hippocampus was also observed. Habenula and amygdala volumes were not different among groups. PD-punding patients showed a cortical thinning of the left superior frontal and precentral gyri and right middle temporal gyrus and isthmus cingulate compared to healthy controls, and of the right inferior frontal gyrus compared to both controls and PD–no ICB patients. Conclusions: A breakdown of the connectivity among the crucial nodes of the reward circuit (i.e., habenula, amygdala, basal ganglia, frontal cortex) might be a contributory factor to punding in PD. This study provides potential instruments to detect and monitor punding in patients with PD.

Psychiatric Symptoms in the Initial Motor Stage of Parkinson's Disease.

Neuropsychiatric symptoms (NPS) are common in Parkinsons disease (PD). The aim of this study was to estimate the correlates of NPS in patients with PD in the initial motor stage of the disease (hemiparkinsonism). A total of 111 patients with PD and 105 healthy control participants were assessed. Patients with PD experienced apathy, depression, and anxiety more frequently compared with healthy controls. Sleep disturbances occurred commonly in early PD patients. Patients with PD and mild cognitive impairment (MCI) had depression and anxiety more frequently, but not apathy, compared with patients with PD without MCI. The results of this study confirm a high burden of NPS even in the earliest motor stage of PD.

Identification of novel variants in LRRK2 gene in patients with Parkinson's disease in Serbian population

BACKGROUND Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most common cause of autosomal dominant Parkinsons disease (PD). Large international studies have revealed that pathogenic mutations are clustered in several exons coding for functional domains of LRRK2 protein, but the mutation frequency differs among populations. Systematic study of LRRK2 mutation prevalence and phenotype in Serbian population has not been performed. METHODS Comprehensive mutation screening of selected exons of LRRK2 was performed in 486 Serbian PD patients. RESULTS Previously reported mutations I1371V and G2019S were identified in a single patient each, and c.4536+3A>G substitution in two patients. G2019S is the most common, pathogenic mutation, while pathogenic roles for recurrent variants I1371V and c.4536+3A>G are not confirmed yet. Two novel variants S1508G and I1991V were discovered in 2 unrelated patients. These variants are considered as disease causing according to several software predictions, but additional segregation and functional analyses are required. CONCLUSIONS Mutation frequency in our study (1.23%) was similar to other European populations, although the most common mutations were underestimated and novel variants were detected. In most cases, symptoms of LRRK2-PD are similar to sporadic PD, so estimation of frequency and penetrance of mutations in different populations is important for efficient genetic testing strategy and counseling.

Identification of mutations in the PARK2 gene in Serbian patients with Parkinson's disease

Mutations in the PARK2 (PRKN) gene are the most common cause of autosomal-recessive (AR) juvenile parkinsonism and young-onset Parkinsons disease (YOPD). >100 different variants have been reported, including point mutations, small indels and single or multiple exon copy number variations. Mutation screening of PARK2 was performed in 225 Serbian PD patients (143 males and 82 females) with disease onset before 50 years and/or positive family history with apparent AR inheritance. All coding regions and their flanking intronic sequences were amplified and directly sequenced. Whole exon multiplications or deletions were detected using Multiple Ligation Probe Amplification (MLPA) method. We identified 12 PD patients with PARK2 mutations (5.3%). Five patients (2.2%) had biallelic mutations and seven (3.1%) were single mutation carriers. Patients with compound heterozygous mutations had earlier onset of the disease compared to non-carriers (p = 0.005) or heterozygotes (p = 0.001). Other clinical features in mutation carriers were not different compared to non-carriers. In our cohort, sequence and dosage variants were equally represented in patients, inducing their first symptoms mainly before the age of 30. For efficient genetic testing strategy, patients with early, especially juvenile onset of PD were strong candidates for both dosage and sequence variants screening of PARK2 gene.

Exploring the relationship between motor impairment, vascular burden and cognition in Parkinson’s disease

ObjectiveTo determine frequency and type of cognitive disorders in cross-sectional analysis of a Parkinson’s disease (PD) cohort, and explore its relations to motor symptoms, modifiable vascular risk factors and white matter lesions (WML) volume.MethodsIn a group of 133 PD patients, mild cognitive impairment (PD-MCI) and dementia (PDD) were diagnosed according to Movement Disorders Society Task Force criteria (level 2 for PD-MCI). Detailed motor measurements were applied, including rigidity, axial, bradykinesia, tremor and postural instability gait disorders (PIGD) scores. Vascular risk was estimated by the Framingham General Cardiovascular Disease risk scoring algorithm and WML volume was measured for whole brain and frontal lobe.ResultsSixty-one (46.9%) patients fulfilled criteria for PD-MCI, and 23 (17.7%) for PDD. Non-amnestic multiple domain MCI was most frequent (52% of PD-MCI patients). Motor scores were significantly higher in cognitively impaired patients, but only axial score discriminated between MCI and dementia. High vascular risk was related to impaired cognition, bradykinesia, axial, PIGD and freezing of gait (FOG) score, while whole brain WML volume was associated with PDD, FOG and attention deficits. Furthermore, high vascular risk was identified as a potential predictor of both MCI and dementia in PD. Additionally, age and bradykinesia score were independently associated with PD-MCI and age, axial score and whole brain WML volume with PDD.ConclusionCognitive disorders in PD are associated with more severe, predominantly axial motor deficits and increased, but partly modifiable vascular burden, thus opening a possibility for development of preventive strategies in PD.

Architecture and partial implementation of the remote monitoring platform for patients with movement disorders

In the coming years, the Internet of Things offers great promises for healhcare. The possibility to remotely monitor patients vital parameters offers a number of benefits: doctors can be aware of patients condition in real time and timely react in the case of emergency. Besides, patients are much more comfortable to stay at homes while avoiding expensive hospitalization costs. In this paper, we propose an architecture of a remote monitoring system for patients with movement disorders. We have developed one of building blocks — wireless inertial sensors platform that can be used in evaluation of therapy effectiveness for patients with spasmodic torticollis. Finally, we have demonstrated the effectiveness of our prototype TremorSense application: by analysing measurements acquired from patients with head dystonic tremor we have numerically confirmed effectiveness of the botulinum toxin injection treatment., In the coming years, the Internet of Things offers great promises for healhcare. The possibility to remotely monitor patients vital parameters offers a number of benefits: doctors can be aware of patients condition in real time and timely react in the case of emergency. Besides, patients are much more comfortable to stay at homes while avoiding expensive hospitalization costs. In this paper, we propose an architecture of a remote monitoring system for patients with movement disorders. We have developed one of building blocks — wireless inertial sensors platform that can be used in evaluation of therapy effectiveness for patients with spasmodic torticollis. Finally, we have demonstrated the effectiveness of our prototype TremorSense application: by analysing measurements acquired from patients with head dystonic tremor we have numerically confirmed effectiveness of the botulinum toxin injection treatment.