Browsing by Author "Kostic, V. (57189017751)"

Unbiased genome-wide screens combined with imaging data on brain function may identify novel molecular pathways related to human cognition. Here we performed a dense genome-wide screen to identify episodic memory-related gene variants. A genomic locus encoding the brain-expressed beta-catenin-like protein 1 (CTNNBL1) was significantly (P=7 × 10 -8) associated with verbal memory performance in a cognitively healthy cohort from Switzerland (n=1073) and was replicated in a second cohort from Serbia (n=524; P=0.003). Gene expression studies showed CTNNBL1 genotype-dependent differences in beta-catenin-like protein 1 mRNA levels in the human cortex. Functional magnetic resonance imaging in 322 subjects detected CTNNBL1 genotype-dependent differences in memory-related brain activations. Converging evidence from independent experiments and different methodological approaches suggests a role for CTNNBL1 in human memory. © 2013 Macmillan Publishers Limited.

Unbiased genome-wide screens combined with imaging data on brain function may identify novel molecular pathways related to human cognition. Here we performed a dense genome-wide screen to identify episodic memory-related gene variants. A genomic locus encoding the brain-expressed beta-catenin-like protein 1 (CTNNBL1) was significantly (P=7 × 10 -8) associated with verbal memory performance in a cognitively healthy cohort from Switzerland (n=1073) and was replicated in a second cohort from Serbia (n=524; P=0.003). Gene expression studies showed CTNNBL1 genotype-dependent differences in beta-catenin-like protein 1 mRNA levels in the human cortex. Functional magnetic resonance imaging in 322 subjects detected CTNNBL1 genotype-dependent differences in memory-related brain activations. Converging evidence from independent experiments and different methodological approaches suggests a role for CTNNBL1 in human memory. © 2013 Macmillan Publishers Limited.

Background and purpose: The aim of the present study was to analyze cerebrospinal fluid (CSF) levels of total tau (T-tau), phosphorylated tau (P-tau) and the 42-amino-acid form of β-amyloid (Aβ42) in patients with myotonic dystrophy type 1 (DM1), and their possible correlations with cognitive and behavioral manifestations in these patients. Methods: Lumbar puncture was performed in 74 patients with DM1 [27 with the childhood/juvenile form (jDM1) and 47 with the adult form (aDM1) of the disease] and 26 control subjects who were subjected to orthopedic surgery. Sandwich ELISA was used for measuring the levels of T-tau, P-tau and Aβ42. Results: The CSF level of Aβ42 was at its lowest in patients with jDM1 and at its highest in controls (P < 0.05). A tendency of T-tau and P-tau to increase was greater in aDM1 patients than in jDM1 patients and controls (P > 0.05). In both jDM1 and aDM1 patients, significant correlations were found between Aβ42 and T-tau (rho = 0.81 and rho = 0.67, respectively, P < 0.01), as well as between Aβ42 and P-tau (rho = 0.87 and rho = 0.67, respectively, P < 0.01). The Aβ42/P-tau ratio decreased with age in aDM1 patients (rho = -0.30, P < 0.05). Only the level of Aβ42 in the CSF of jDM1 patients was correlated with the size of the CTG expansion (rho = -0.53, P < 0.05). Only a few correlations were observed between levels of biomarkers and neuropsychological testing. Conclusion: The CSF level of Aβ42 was decreased in patients with jDM1, whilst the Aβ42/P-tau ratio was decreased in aDM1 patients. Positive correlations between Aβ42, T-tau and P-tau were observed in both forms of disease. Further studies with larger cohorts of DM1 patients are necessary. © 2013 The Author(s) European Journal of Neurology © 2013 EFNS.

Background and purpose: The aim of the present study was to analyze cerebrospinal fluid (CSF) levels of total tau (T-tau), phosphorylated tau (P-tau) and the 42-amino-acid form of β-amyloid (Aβ42) in patients with myotonic dystrophy type 1 (DM1), and their possible correlations with cognitive and behavioral manifestations in these patients. Methods: Lumbar puncture was performed in 74 patients with DM1 [27 with the childhood/juvenile form (jDM1) and 47 with the adult form (aDM1) of the disease] and 26 control subjects who were subjected to orthopedic surgery. Sandwich ELISA was used for measuring the levels of T-tau, P-tau and Aβ42. Results: The CSF level of Aβ42 was at its lowest in patients with jDM1 and at its highest in controls (P < 0.05). A tendency of T-tau and P-tau to increase was greater in aDM1 patients than in jDM1 patients and controls (P > 0.05). In both jDM1 and aDM1 patients, significant correlations were found between Aβ42 and T-tau (rho = 0.81 and rho = 0.67, respectively, P < 0.01), as well as between Aβ42 and P-tau (rho = 0.87 and rho = 0.67, respectively, P < 0.01). The Aβ42/P-tau ratio decreased with age in aDM1 patients (rho = -0.30, P < 0.05). Only the level of Aβ42 in the CSF of jDM1 patients was correlated with the size of the CTG expansion (rho = -0.53, P < 0.05). Only a few correlations were observed between levels of biomarkers and neuropsychological testing. Conclusion: The CSF level of Aβ42 was decreased in patients with jDM1, whilst the Aβ42/P-tau ratio was decreased in aDM1 patients. Positive correlations between Aβ42, T-tau and P-tau were observed in both forms of disease. Further studies with larger cohorts of DM1 patients are necessary. © 2013 The Author(s) European Journal of Neurology © 2013 EFNS.

Background: A Task Force was convened by the EFNS/MDS-ES Scientist Panel on Parkinson's disease (PD) and other movement disorders to systemically review relevant publications on the diagnosis of PD. Methods: Following the EFNS instruction for the preparation of neurological diagnostic guidelines, recommendation levels have been generated for diagnostic criteria and investigations. Results: For the clinical diagnosis, we recommend the use of the Queen Square Brain Bank criteria (Level B). Genetic testing for specific mutations is recommended on an individual basis (Level B), taking into account specific features (i.e. family history and age of onset). We recommend olfactory testing to differentiate PD from other parkinsonian disorders including recessive forms (Level A). Screening for pre-motor PD with olfactory testing requires additional tests due to limited specificity. Drug challenge tests are not recommended for the diagnosis in de novo parkinsonian patients. There is an insufficient evidence to support their role in the differential diagnosis between PD and other parkinsonian syndromes. We recommend an assessment of cognition and a screening for REM sleep behaviour disorder, psychotic manifestations and severe depression in the initial evaluation of suspected PD cases (Level A). Transcranial sonography is recommended for the differentiation of PD from atypical and secondary parkinsonian disorders (Level A), for the early diagnosis of PD and in the detection of subjects at risk for PD (Level A), although the technique is so far not universally used and requires some expertise. Because specificity of TCS for the development of PD is limited, TCS should be used in conjunction with other screening tests. Conventional magnetic resonance imaging and diffusion-weighted imaging at 1.5 T are recommended as neuroimaging tools that can support a diagnosis of multiple system atrophy (MSA) or progressive supranuclear palsy versus PD on the basis of regional atrophy and signal change as well as diffusivity patterns (Level A). DaTscan SPECT is registered in Europe and the United States for the differential diagnosis between degenerative parkinsonisms and essential tremor (Level A). More specifically, DaTscan is indicated in the presence of significant diagnostic uncertainty such as parkinsonism associated with neuroleptic exposure and atypical tremor manifestations such as isolated unilateral postural tremor. Studies of [123I]MIBG/SPECT cardiac uptake may be used to identify patients with PD versus controls and MSA patients (Level A). All other SPECT imaging studies do not fulfil registration standards and cannot be recommended for routine clinical use. At the moment, no conclusion can be drawn as to diagnostic efficacy of autonomic function tests, neurophysiological tests and positron emission tomography imaging in PD. Conclusions: The diagnosis of PD is still largely based on the correct identification of its clinical features. Selected investigations (genetic, olfactory, and neuroimaging studies) have an ancillary role in confirming the diagnosis, and some of them could be possibly used in the near future to identify subjects in a pre-symptomatic phase of the disease. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS European Journal of Neurology.

Background: A Task Force was convened by the EFNS/MDS-ES Scientist Panel on Parkinson's disease (PD) and other movement disorders to systemically review relevant publications on the diagnosis of PD. Methods: Following the EFNS instruction for the preparation of neurological diagnostic guidelines, recommendation levels have been generated for diagnostic criteria and investigations. Results: For the clinical diagnosis, we recommend the use of the Queen Square Brain Bank criteria (Level B). Genetic testing for specific mutations is recommended on an individual basis (Level B), taking into account specific features (i.e. family history and age of onset). We recommend olfactory testing to differentiate PD from other parkinsonian disorders including recessive forms (Level A). Screening for pre-motor PD with olfactory testing requires additional tests due to limited specificity. Drug challenge tests are not recommended for the diagnosis in de novo parkinsonian patients. There is an insufficient evidence to support their role in the differential diagnosis between PD and other parkinsonian syndromes. We recommend an assessment of cognition and a screening for REM sleep behaviour disorder, psychotic manifestations and severe depression in the initial evaluation of suspected PD cases (Level A). Transcranial sonography is recommended for the differentiation of PD from atypical and secondary parkinsonian disorders (Level A), for the early diagnosis of PD and in the detection of subjects at risk for PD (Level A), although the technique is so far not universally used and requires some expertise. Because specificity of TCS for the development of PD is limited, TCS should be used in conjunction with other screening tests. Conventional magnetic resonance imaging and diffusion-weighted imaging at 1.5 T are recommended as neuroimaging tools that can support a diagnosis of multiple system atrophy (MSA) or progressive supranuclear palsy versus PD on the basis of regional atrophy and signal change as well as diffusivity patterns (Level A). DaTscan SPECT is registered in Europe and the United States for the differential diagnosis between degenerative parkinsonisms and essential tremor (Level A). More specifically, DaTscan is indicated in the presence of significant diagnostic uncertainty such as parkinsonism associated with neuroleptic exposure and atypical tremor manifestations such as isolated unilateral postural tremor. Studies of [123I]MIBG/SPECT cardiac uptake may be used to identify patients with PD versus controls and MSA patients (Level A). All other SPECT imaging studies do not fulfil registration standards and cannot be recommended for routine clinical use. At the moment, no conclusion can be drawn as to diagnostic efficacy of autonomic function tests, neurophysiological tests and positron emission tomography imaging in PD. Conclusions: The diagnosis of PD is still largely based on the correct identification of its clinical features. Selected investigations (genetic, olfactory, and neuroimaging studies) have an ancillary role in confirming the diagnosis, and some of them could be possibly used in the near future to identify subjects in a pre-symptomatic phase of the disease. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS European Journal of Neurology.

Background and purpose: To screen for glucocerebrosidase (GBA) mutations in a Serbian Parkinson's disease (PD) population. Methods: Glucocerebrosidase exons 8-11 harbouring the most common mutations were sequenced in 360 patients with PD and 348 controls from Serbia. Haplotype analysis was performed for the N370S mutation and compared with German and Ashkenazi Jewish carriers. Results: Glucocerebrosidase mutations were significantly more frequent in patients with PD (21/360; 5.8%) vs. controls (5/348; 1.4%; OR = 4.25; CI, 1.58-11.40; P = 0.0041). Two patients with PD carried homozygous or compound heterozygous mutations in GBA. The N370S mutation accounted for about half of the mutated alleles in patients (10/23) but was absent amongst controls. Three novel variants were detected including two non-synonymous variants (D380V, N392S) in the patient group and one synonymous change (V459V) in a control. Carriers of the D409H mutation were also sequenced for H255Q, and all were found to carry the [D409H; H255Q] double-mutant allele. Genotyping suggested a common haplotype for all N370S carriers. Conclusion: Glucocerebrosidase mutations represent a PD risk factor in the Serbian population. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

Background and purpose: To screen for glucocerebrosidase (GBA) mutations in a Serbian Parkinson's disease (PD) population. Methods: Glucocerebrosidase exons 8-11 harbouring the most common mutations were sequenced in 360 patients with PD and 348 controls from Serbia. Haplotype analysis was performed for the N370S mutation and compared with German and Ashkenazi Jewish carriers. Results: Glucocerebrosidase mutations were significantly more frequent in patients with PD (21/360; 5.8%) vs. controls (5/348; 1.4%; OR = 4.25; CI, 1.58-11.40; P = 0.0041). Two patients with PD carried homozygous or compound heterozygous mutations in GBA. The N370S mutation accounted for about half of the mutated alleles in patients (10/23) but was absent amongst controls. Three novel variants were detected including two non-synonymous variants (D380V, N392S) in the patient group and one synonymous change (V459V) in a control. Carriers of the D409H mutation were also sequenced for H255Q, and all were found to carry the [D409H; H255Q] double-mutant allele. Genotyping suggested a common haplotype for all N370S carriers. Conclusion: Glucocerebrosidase mutations represent a PD risk factor in the Serbian population. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

Mutations in the PARK2 (PRKN) gene are the most common cause of autosomal-recessive (AR) juvenile parkinsonism and young-onset Parkinson's 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. © 2018 Elsevier B.V.

Mutations in the PARK2 (PRKN) gene are the most common cause of autosomal-recessive (AR) juvenile parkinsonism and young-onset Parkinson's 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. © 2018 Elsevier B.V.

Objective: To summarize the 2010 EFNS/MDS-ES evidence-based treatment recommendations for the management of Parkinson's disease (PD). This summary includes the treatment recommendations for early and late PD. Methods: For the 2010 publication, a literature search was undertaken for articles published up to September 2009. For this summary, an additional literature search was undertaken up to December 2010. Classification of scientific evidence and the rating of recommendations were made according to the EFNS guidance. In cases where there was insufficient scientific evidence, a consensus statement ('good practice point') is made. Results and Conclusions: For each clinical indication, a list of therapeutic interventions is provided, including classification of evidence. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

Objective: To summarize the 2010 EFNS/MDS-ES evidence-based treatment recommendations for the management of Parkinson's disease (PD). This summary includes the treatment recommendations for early and late PD. Methods: For the 2010 publication, a literature search was undertaken for articles published up to September 2009. For this summary, an additional literature search was undertaken up to December 2010. Classification of scientific evidence and the rating of recommendations were made according to the EFNS guidance. In cases where there was insufficient scientific evidence, a consensus statement ('good practice point') is made. Results and Conclusions: For each clinical indication, a list of therapeutic interventions is provided, including classification of evidence. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

Background: The vascular risk factors are associated with an increased risk for vascular cognitive decline (VCD), but also with Alzheimer disease (AD). Objective: To investigate vascular risk factors in relation to AD and VCD, with a non-invasive neurosonological methods in a clinical settings. Results: A total of 296 patients with AD and 237 patients with VCD were included in the study. Hypertension, hyperlipidemia, diabetes mellitus, stroke, and white matter changes (p < 0.001) were significantly more prevalent in VCD, although they were also present in AD patients. No statistically significant differences were obtained between groups regarding coronary disease, atrial fibrillation, average degree of carotid artery stenosis and carotid intima-media thickness (cITM). However, the patients with AD had carotid artery stenosis > 50% (p = 0.007) and present plaques (p < 0.001) more frequently compared to vascular group. The significant associations between robust cognitive measure and vascular factors, diabetes mellitus, carotid stenosis, cITM, and type of plaques were identified only in VCD, but not in AD group. Conclusions: The vascular risk factors were more prevalent in VCD group, although they were also present in AD. With few treatment options available in AD, it may be important not to neglect the vascular risk factors. © 2012 Elsevier B.V.

Background: The vascular risk factors are associated with an increased risk for vascular cognitive decline (VCD), but also with Alzheimer disease (AD). Objective: To investigate vascular risk factors in relation to AD and VCD, with a non-invasive neurosonological methods in a clinical settings. Results: A total of 296 patients with AD and 237 patients with VCD were included in the study. Hypertension, hyperlipidemia, diabetes mellitus, stroke, and white matter changes (p < 0.001) were significantly more prevalent in VCD, although they were also present in AD patients. No statistically significant differences were obtained between groups regarding coronary disease, atrial fibrillation, average degree of carotid artery stenosis and carotid intima-media thickness (cITM). However, the patients with AD had carotid artery stenosis > 50% (p = 0.007) and present plaques (p < 0.001) more frequently compared to vascular group. The significant associations between robust cognitive measure and vascular factors, diabetes mellitus, carotid stenosis, cITM, and type of plaques were identified only in VCD, but not in AD group. Conclusions: The vascular risk factors were more prevalent in VCD group, although they were also present in AD. With few treatment options available in AD, it may be important not to neglect the vascular risk factors. © 2012 Elsevier B.V.