These include, among others, two forms of atypical Parkinsonism, multiple system atrophy (MSA) an... more These include, among others, two forms of atypical Parkinsonism, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). This study aimed to assess the potential role of C9orf72 repeat expansions among Serbian patients diagnosed with MSA and PSP. Genomic DNA of 44 MSA patients, 73 PSP patients, and 96 controls was extracted from peripheral blood, and normal C9orf72 alleles were analyzed by standard quantitative fluorescence polymerase chain reaction (QF-PCR) and fragment analysis. Subsequently, for all samples presenting a single allele, repeat-primed PCR was performed with two different sets of primers to avoid a false-negative result. Thirty repeats were used as a pathogenic cut-off and 20-29 repeats for the intermediate alleles. No pathological C9orf72 expansions were detected in the MSA and PSP patients nor the control subjects. In the MSA group, the most common was the allele with 2 repeats, and the largest repeat number was 14. Among PSP patients, the most common allele also had 2 repeats, while the largest detected repeat size within the normal range was 17. Also, we identified one PSP patient that had an intermediate size allele (25 repeats). We did not find correlation between the number of repeats and disease onset, age at the time of examination, or disease duration in MSA or PSP patients. Regarding family history, in PSP the sum of both allele repeats numbers was higher in patients with positive family history than in sporadic cases. The results presented in this study are the first systematic assessment of C9orf72 allele sizes among patients diagnosed with MSA and PSP in the Serbian population. Although the potential role of intermediate C9orf72 repeats in neurodegenerative disorders is still to be elucidated, our results support the current knowledge that C9orf72 repeat expansions are not associated with MSA and PSP.
As life span rises, dementia has become a growing public health issue. According to current estim... more As life span rises, dementia has become a growing public health issue. According to current estimates, almost 50 million people worldwide have dementia, and the number is expected to grow. Next generation sequencing (NGS) methods have helped significantly with identifying causative gene variants related to various cognitive disorders. Our study aimed to analyze the genetic basis of cognitive disorders using NGS clinical exome panel. The study included a total number of 15 unrelated cases diagnosed with cognitive disorders, all negative after standard targeted genetic testing was performed (available at Neurology Clinic, UCCS, Belgrade, Serbia). Preference was given to familial cases with early presentation or complex phenotype. Sequencing of a clinical exome (CE) panel for 4813 genes with known associated clinical phenotypes was performed using TruSight One sequencing panel on an Illumina MiSeq NGS platform according to the manufacturer's instructions (Illumina, San Diego, CA, USA). Variants were analyzed with Illumina Variant Studio v3 software provided by Illumina as well as a previously developed pipeline. Variants analysis and interpretation were based on phenotype gene target approach, literature and databases search, allele frequency, and pathogenicity prediction by in silico software. All causative variants were confirmed by Sanger sequencing. Whenever possible, additional family members were studied for segregation analysis. CE panel analysis revealed a likely genetic cause in four patients. We have 1352
Zunera Khan, Anne Corbett, South London and Maudsley NHS Foundation Trust, London, United Kingdom... more Zunera Khan, Anne Corbett, South London and Maudsley NHS Foundation Trust, London, United Kingdom; King’s College London, London, United Kingdom; University of Exeter Medical School, Exeter, United Kingdom; Oxford Health NHS Trust, Oxford, United Kingdom; Institute of Mental Health, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, United Kingdom; Institute of Rehabilitation, Dementia Applied Research Centre, University of Hull, Hull, United Kingdom; Institute of Medical and Social Care Research, Bangor University, Bangor, United Kingdom; King’s College London, London, United Kingdom; Whitaker Research Ltd, Bangor, United Kingdom; Oxford Health NHS Foundation Trust, Oxford, United Kingdom; London School of Economics and Political Science, London, United Kingdom. Contact e-mail: [email protected]
Parkinson's disease (PD) patients can be classified in tremor-dominant (TD) and postural-instabil... more Parkinson's disease (PD) patients can be classified in tremor-dominant (TD) and postural-instability-and-gait-disorder (PIGD) motor subtypes. PIGD represents a more aggressive form of the disease that TD patients have a potentiality of converting into. This study investigated functional alterations within the cerebro-cerebellar system in PD-TD and PD-PIGD patients using stepwise functional connectivity (SFC) analysis and identified neuroimaging features that predict TD to PIGD conversion. Thirty-two PD-TD, 26 PD-PIGD patients and 60 healthy controls performed clinical/cognitive evaluations and resting-state functional MRI (fMRI). Four-year clinical follow-up data were available for 28 PD-TD patients, who were classified in 10 converters (cTD-PD) and 18 non-converters (ncTD-PD) to PIGD. The cerebellar seed-region was identified using a fMRI motor task. SFC analysis, characterizing regions that connect brain areas to the cerebellar seed at different levels of link-step distances, evaluated similar and divergent alterations in PD-TD and PD-PIGD. The discriminatory power of clinical data and/or SFC in distinguishing cPD-TD from ncPD-TD patients was assessed using ROC curve analysis. Compared to PD-TD, PD-PIGD patients showed decreased SFC in temporal lobe and occipital lobes and increased SFC in cerebellar cortex and ponto-medullary junction. Considering the subtype-conversion analysis, cPD-TD patients were characterized by increased SFC in temporal and occipital lobes and in cerebellum and ponto-medullary junction relative to ncPD-TD group. Combining clinical and SFC data, ROC curves provided the highest classification power to identify conversion to PIGD. These findings provide novel insights into the pathophysiology underlying different PD motor phenotypes and a potential tool for early characterization of PD-TD patients at risk of conversion to PIGD.
The relative frequencies of different spinocerebellar ataxias (SCAs) vary widely among different ... more The relative frequencies of different spinocerebellar ataxias (SCAs) vary widely among different ethnic groups, presumably due to a founder effect. We investigated the relative prevalence of SCA1-3, 6-8, 12, 17; dentate-rubro-pallidoluysian atrophy; and Friedreich's ataxia (FRDA) in Serbian patients with adult-onset (Ͼ20 years of age) hereditary and sporadic SCAs, and compared clinical features of patients with genetically confirmed SCAs. A total of 108 patients from 54 families (38 apparently dominant [ADCA] and 16 apparently recessive) with adult-onset hereditary ataxia and 75 apparently sporadic patients were assessed. Of 38 families with ADCA, 13 (34%) were positive for an expansion in an SCA1 and 5 families (13%) for an expansion in an SCA2 allele. In 20 families (53%), no expansions have been identified in any of the analyzed genes. Gaze palsy, spasticity, and hyperreflexia were significantly more common in SCA1, whereas slow saccades, hypotonia, hyporeflexia, and dystonia prevailed in SCA2 patients. Among the 16 families with an apparently recessive mode of ataxia inheritance, 4 (25%) were identified as having the FRDA mutation. Ataxia-causing mutations were identified in 8 (10.6%) of patients with apparently sporadic adult-onset ataxia.
A BS TRACT: Background: The objectives of this study were to investigate progressive cortical thi... more A BS TRACT: Background: The objectives of this study were to investigate progressive cortical thinning and volume loss in Parkinson's disease (PD) patients with different longitudinal patterns of cognitive decline: with stable normal cognition, with stable mild cognitive impairment, with conversion to mild cognitive impairment, and with conversion to dementia. Methods: We recruited 112 patients (37 Parkinson's disease with stable normal cognition, 20 Parkinson's disease with stable mild cognitive impairment, 36 Parkinson's disease with conversion to mild cognitive impairment, 19 Parkinson's disease with conversion to dementia) and 38 healthy controls. All patients underwent at least 2 visits within 4 years including clinical/cognitive assessments and structural MRI (total visits, 393). Baseline cortical thickness and gray matter volumetry were compared between groups. In PD, gray matter changes over time were investigated and compared between groups. Results: At baseline, compared with Parkinson's disease with stable normal cognition cases, Parkinson's disease with conversion to mild cognitive impairment patients showed cortical atrophy of the parietal and occipital lobes, similar to Parkinson's disease with stable mild cognitive impairment and Parkinson's disease with conversion to dementia patients. The latter groups (ie, patients with cognitive impairment from the study entry) showed additional involvement of the frontotemporal cortices. No baseline volumetric differences among groups were detected. The longitudinal analysis (group-by-time interaction) showed that, versus the other patient groups, Parkinson's disease with stable mild cognitive impairment and Parkinson's disease with conversion to dementia cases accumulated the least cortical damage, with Parkinson's disease with conversion to dementia showing unique progression of right thalamic and hippocampal volume loss; Parkinson's disease with conversion to mild cognitive impairment patients showing specific cortical thinning accumulation in the medial and superior frontal gyri, inferior temporal, precuneus, posterior cingulum, and supramarginal gyri bilaterally; and Parkinson's disease with stable normal cognition patients showing cortical thinning progression, mainly in the occipital and parietal regions bilaterally. Conclusions: Cortical thinning progression is more prominent in the initial stages of PD cognitive decline. The involvement of frontotemporoparietal regions, the hippocampus, and the thalamus is associated with conversion to a more severe stage of cognitive impairment. In PD, gray matter alterations of critical brain regions may be an MRI signature for the identification of patients at risk of developing dementia.
This study assesses the patterns of gray matter (GM) and white matter (WM) damage in patients wit... more This study assesses the patterns of gray matter (GM) and white matter (WM) damage in patients with Parkinson's disease and mild cognitive impairment (PD-MCI) compared with healthy controls and cognitively unimpaired PD patients (PD-Cu). Three-dimensional T1-weighted and diffusion tensor (DT) magnetic resonance imaging (MRI) scans were obtained from 43 PD patients and 33 healthy controls. Cognition was assessed using a neuropsychological battery. Tract-based spatial statistics was applied to compare DT MRI indices between groups on a voxel-by-voxel basis. Voxel-based morphometry was performed to assess GM atrophy. Thirty PD patients were classified as MCI. Compared with healthy controls, PD-Cu and PD-MCI patients did not have GM atrophy. No region of WM damage was found in PD-Cu patients when compared with healthy controls. Relative to healthy controls and PD-Cu patients, PD-MCI patients showed a distributed pattern of WM abnormalities in the anterior and superior corona radiata, genu, and body of the corpus callosum, and anterior inferior fronto-occipital, uncinate, and superior longitudinal fasciculi, bilaterally. Subtle cognitive decline in PD is associated with abnormalities of frontal and interhemispheric WM connections, and not with GM atrophy. DT MRI might contribute to the identification of structural changes in PD-MCI patients prior to the development of dementia.
This study aimed to identify functional neuroimaging patterns anticipating the clinical indicatio... more This study aimed to identify functional neuroimaging patterns anticipating the clinical indication for deep brain stimulation (DBS) in patients with Parkinson's disease (PD). A cohort of prospectively recruited patients with PD underwent neurological evaluations and resting-state functional MRI (RS-fMRI) at baseline and annually for 4 years. Patients were divided into two groups: 19 patients eligible for DBS over the follow-up and 41 patients who did not meet the criteria to undergo DBS. Patients selected as candidates for DBS did not undergo surgery at this stage. Sixty age-and sex-matched healthy controls performed baseline evaluations. Graph analysis and connectomics assessed global and local topological network properties and regional functional connectivity at baseline and at each time point. At baseline, network analysis showed a higher mean nodal strength, local efficiency, and clustering coefficient of the occipital areas in candidates for DBS over time relative to controls and patients not eligible for DBS. The occipital hyperconnectivity pattern was confirmed by regional analysis. At baseline, a decreased functional connectivity between basal ganglia and sensorimotor/frontal networks was found in candidates for DBS compared to patients not eligible for surgery. In the longitudinal analysis, patient candidate for DBS showed a progressively decreased topological brain organization and functional connectivity, mainly in the posterior brain networks, and a progressively increased connectivity of basal ganglia network compared to non-candidates for DBS. RS-fMRI may support the clinical indication to DBS and could be useful in predicting which patients would be eligible for DBS in the earlier stages of PD.
BackgroundEarly‐onset dementia (EOD) is conventionally considered to include patients with diseas... more BackgroundEarly‐onset dementia (EOD) is conventionally considered to include patients with disease onset before 65 years of age. Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) are two most common forms of degenerative EOD. Our aim was to screen for known gene mutation status in consecutive degenerative EOD patients.MethodTwo hundred and eight consecutive patients diagnosed according to the current clinical criteria for AD and FTD spectrum were recruited from the Neurology Clinic, Clinical Centre of Serbia from 01.04.2012. until 01.04.2017. Patient from AD spectrum were tested for APP, PSEN1, GRN, MAPT and C9ORF72 gene mutation and FTD patients for GRN, MAPT, C9ORF72, VCP, ANG gene mutation.ResultGene mutations were identified in 3.9% of our AD patients: 2.3% patients had mutations in the PSEN1 gene and 1.5% patients in the APP gene. There was no MAPT, GRN and C9ORF72 mutations carriers in our AD cohort. Genetic mutations have been demonstrated in 10.3% of patients with F...
BackgroundThe aim of the present study was to examine cognitive‐behavioral changes that may be re... more BackgroundThe aim of the present study was to examine cognitive‐behavioral changes that may be related to the lockdown and the quarantine during the COVID‐19 pandemic in Serbian patients with mild cognitive impairment (MCI), and Alzheimer dementia (AD). The caregivers’ distress was also evaluated.MethodThe 2089 registered patients with cognitive deficits, between December 2018 until January 2020 in Belgrade Memory clinic registry, University Clinical Center was contacted by telephone within the survey, 2 months after the lockdown declaration. Either the patients or their caregivers were asked to answer on: Caregiver Questionnaire, the Kingston Caregiver Stress Scale, Patient Questionnaire, Neuropsychiatric Questionnaire, and Clinical Dementia rating scale for caregiver and patients.ResultThe study included 1002 (females 56.%) patients either with AD (n = 389) or MCI (n = 604) who have got completed data set for analyses. Unfortunately, 74 patients died in the pandemic time, and 225 ...
This study investigated longitudinal clinical, structural and functional brain alterations in Par... more This study investigated longitudinal clinical, structural and functional brain alterations in Parkinson’s disease patients with freezing of gait (PD-FoG) and in those developing (PD-FoG-converters) and not developing FoG (PD-non-converters) over two years. Moreover, this study explored if any clinical and/or MRI metric predicts FoG development. Thirty PD-FoG, 11 PD-FoG-converters and 11 PD-non-converters were followed for two years. Thirty healthy controls were included at baseline. Participants underwent clinical and MRI visits. Cortical thickness, basal ganglia volumes and functional network graph metrics were evaluated at baseline and over time. In PD groups, correlations between baseline MRI and clinical worsening were tested. A ROC curve analysis investigated if baseline clinical and MRI measures, selected using a stepwise model procedure, could differentiate PD-FoG-converters from PD-non-converters. At baseline, PD-FoG patients had widespread cortical/subcortical atrophy, whil...
ABSTRACTBackgroundWhite matter hyperintensities (WMHs) have a role in cognitive impairment in nor... more ABSTRACTBackgroundWhite matter hyperintensities (WMHs) have a role in cognitive impairment in normal brain aging, while the effect on Parkinson's disease (PD) progression is still controversial.ObjectiveTo investigate the longitudinal evolution of micro‐ and macrostructural damage of cerebral white matter (WM) and its relationship with the clinical picture in PD.MethodsA total of 154 PD patients underwent clinical, cognitive, and magnetic resonance imaging (MRI) assessment once a year for up to 4 years. Sixty healthy controls underwent the same protocol at baseline. WMHs were identified and total WMH volume was measured. WMHs were also used as exclusion masks to define normal‐appearing white matter (NAWM). Using tract‐based spatial statistics, diffusion tensor (DT) MRI metrics of whole‐brain WM and NAWM were obtained. Linear mixed‐effects models defined the longitudinal evolution and association between variables. WM alterations were tested as risk factors of disease progression...
BackgroundTo investigate functional alterations in the cerebro‐cerebellar system in two Parkinson... more BackgroundTo investigate functional alterations in the cerebro‐cerebellar system in two Parkinson’s disease (PD) clinical phenotypes (tremor‐dominant [TD] and postural instability and gait disorder [PIGD]using stepwise functional connectivity (SFC).Method58 PD patients performed clinical and cognitive evaluations and resting‐state functional MRI (fMRI). PD cohort was divided into two groups: 32 patients with TD (PD‐TD) and 26 with PIGD (PD‐PIGD). 60 age‐ and sex‐matched healthy controls were also enrolled. SFC analysis aims to characterize regions that connect to specific seed brain areas at different levels of link‐step distances. The cerebellar seed‐region was identified using motor task‐based fMRI in 23 controls. For each of the SFC maps, whole‐brain two‐sample t‐test comparisons between groups were performed.ResultThe performance of the motor task during fMRI was associated with activation of the lobule VI and vermis of the cerebellum. SFC analysis at one‐link step distance show...
Objective: To investigate functional neural pathway organization and changes over-time in patient... more Objective: To investigate functional neural pathway organization and changes over-time in patients with Parkinson’s disease (PD) using advanced network-based techniques. Background: Graph theoretical analyses and network science are powerful tools to study functional organization of the brain. Design/Methods: 146 PD patients performed clinical and cognitive evaluations and resting-state functional MRI at baseline and every year for 4 years. Hierarchical cluster analysis identified two PD subtypes: 86 “early” and 60 “mild-to-severe” patients. Within the “early” subtype, two clinical groups were identified: “early-motor-predominant” and “early-diffuse”, the latter having greater cognitive deficits and more frequent non-motor manifestations. 60 age- and sex-matched controls performed baseline assessments. Graph analysis and connectomics assessed global and local topological network properties and regional functional connectivity (FC) at baseline and changes over-time. Results: “Early” ...
Objective.To detect the structural brain signatures of patients with a late age-of-onset major de... more Objective.To detect the structural brain signatures of patients with a late age-of-onset major depressive disorder (lo-MDD) relative to controls (training-dataset), and to test the ability of such measures to predict the presence of depression in Alzheimer’s disease (AD) and behavioral variant of frontotemporal dementia (bvFTD) (testing-dataset). Background.Whether depressive symptoms are intrinsic to neurodegeneration is still poorly understood. Lo-MDD may represent a model to understand the nature of depressive symptoms in AD and bvFTD. Methods.T1-weighted and diffusion tensor (DT)-MRI were obtained from 15 lo-MDD and 28 controls, and from an age-matched dataset of 61 AD and 27 bvFTD patients. Participants underwent a clinical assessment to detect the presence of depression. Cortical thickness (CT) and white matter (WM) metrics were obtained from all subjects, and compared among training-dataset groups to identify signatures of depression. MRI measures found to be significantly di...
These include, among others, two forms of atypical Parkinsonism, multiple system atrophy (MSA) an... more These include, among others, two forms of atypical Parkinsonism, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). This study aimed to assess the potential role of C9orf72 repeat expansions among Serbian patients diagnosed with MSA and PSP. Genomic DNA of 44 MSA patients, 73 PSP patients, and 96 controls was extracted from peripheral blood, and normal C9orf72 alleles were analyzed by standard quantitative fluorescence polymerase chain reaction (QF-PCR) and fragment analysis. Subsequently, for all samples presenting a single allele, repeat-primed PCR was performed with two different sets of primers to avoid a false-negative result. Thirty repeats were used as a pathogenic cut-off and 20-29 repeats for the intermediate alleles. No pathological C9orf72 expansions were detected in the MSA and PSP patients nor the control subjects. In the MSA group, the most common was the allele with 2 repeats, and the largest repeat number was 14. Among PSP patients, the most common allele also had 2 repeats, while the largest detected repeat size within the normal range was 17. Also, we identified one PSP patient that had an intermediate size allele (25 repeats). We did not find correlation between the number of repeats and disease onset, age at the time of examination, or disease duration in MSA or PSP patients. Regarding family history, in PSP the sum of both allele repeats numbers was higher in patients with positive family history than in sporadic cases. The results presented in this study are the first systematic assessment of C9orf72 allele sizes among patients diagnosed with MSA and PSP in the Serbian population. Although the potential role of intermediate C9orf72 repeats in neurodegenerative disorders is still to be elucidated, our results support the current knowledge that C9orf72 repeat expansions are not associated with MSA and PSP.
As life span rises, dementia has become a growing public health issue. According to current estim... more As life span rises, dementia has become a growing public health issue. According to current estimates, almost 50 million people worldwide have dementia, and the number is expected to grow. Next generation sequencing (NGS) methods have helped significantly with identifying causative gene variants related to various cognitive disorders. Our study aimed to analyze the genetic basis of cognitive disorders using NGS clinical exome panel. The study included a total number of 15 unrelated cases diagnosed with cognitive disorders, all negative after standard targeted genetic testing was performed (available at Neurology Clinic, UCCS, Belgrade, Serbia). Preference was given to familial cases with early presentation or complex phenotype. Sequencing of a clinical exome (CE) panel for 4813 genes with known associated clinical phenotypes was performed using TruSight One sequencing panel on an Illumina MiSeq NGS platform according to the manufacturer's instructions (Illumina, San Diego, CA, USA). Variants were analyzed with Illumina Variant Studio v3 software provided by Illumina as well as a previously developed pipeline. Variants analysis and interpretation were based on phenotype gene target approach, literature and databases search, allele frequency, and pathogenicity prediction by in silico software. All causative variants were confirmed by Sanger sequencing. Whenever possible, additional family members were studied for segregation analysis. CE panel analysis revealed a likely genetic cause in four patients. We have 1352
Zunera Khan, Anne Corbett, South London and Maudsley NHS Foundation Trust, London, United Kingdom... more Zunera Khan, Anne Corbett, South London and Maudsley NHS Foundation Trust, London, United Kingdom; King’s College London, London, United Kingdom; University of Exeter Medical School, Exeter, United Kingdom; Oxford Health NHS Trust, Oxford, United Kingdom; Institute of Mental Health, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, United Kingdom; Institute of Rehabilitation, Dementia Applied Research Centre, University of Hull, Hull, United Kingdom; Institute of Medical and Social Care Research, Bangor University, Bangor, United Kingdom; King’s College London, London, United Kingdom; Whitaker Research Ltd, Bangor, United Kingdom; Oxford Health NHS Foundation Trust, Oxford, United Kingdom; London School of Economics and Political Science, London, United Kingdom. Contact e-mail: [email protected]
Parkinson's disease (PD) patients can be classified in tremor-dominant (TD) and postural-instabil... more Parkinson's disease (PD) patients can be classified in tremor-dominant (TD) and postural-instability-and-gait-disorder (PIGD) motor subtypes. PIGD represents a more aggressive form of the disease that TD patients have a potentiality of converting into. This study investigated functional alterations within the cerebro-cerebellar system in PD-TD and PD-PIGD patients using stepwise functional connectivity (SFC) analysis and identified neuroimaging features that predict TD to PIGD conversion. Thirty-two PD-TD, 26 PD-PIGD patients and 60 healthy controls performed clinical/cognitive evaluations and resting-state functional MRI (fMRI). Four-year clinical follow-up data were available for 28 PD-TD patients, who were classified in 10 converters (cTD-PD) and 18 non-converters (ncTD-PD) to PIGD. The cerebellar seed-region was identified using a fMRI motor task. SFC analysis, characterizing regions that connect brain areas to the cerebellar seed at different levels of link-step distances, evaluated similar and divergent alterations in PD-TD and PD-PIGD. The discriminatory power of clinical data and/or SFC in distinguishing cPD-TD from ncPD-TD patients was assessed using ROC curve analysis. Compared to PD-TD, PD-PIGD patients showed decreased SFC in temporal lobe and occipital lobes and increased SFC in cerebellar cortex and ponto-medullary junction. Considering the subtype-conversion analysis, cPD-TD patients were characterized by increased SFC in temporal and occipital lobes and in cerebellum and ponto-medullary junction relative to ncPD-TD group. Combining clinical and SFC data, ROC curves provided the highest classification power to identify conversion to PIGD. These findings provide novel insights into the pathophysiology underlying different PD motor phenotypes and a potential tool for early characterization of PD-TD patients at risk of conversion to PIGD.
The relative frequencies of different spinocerebellar ataxias (SCAs) vary widely among different ... more The relative frequencies of different spinocerebellar ataxias (SCAs) vary widely among different ethnic groups, presumably due to a founder effect. We investigated the relative prevalence of SCA1-3, 6-8, 12, 17; dentate-rubro-pallidoluysian atrophy; and Friedreich's ataxia (FRDA) in Serbian patients with adult-onset (Ͼ20 years of age) hereditary and sporadic SCAs, and compared clinical features of patients with genetically confirmed SCAs. A total of 108 patients from 54 families (38 apparently dominant [ADCA] and 16 apparently recessive) with adult-onset hereditary ataxia and 75 apparently sporadic patients were assessed. Of 38 families with ADCA, 13 (34%) were positive for an expansion in an SCA1 and 5 families (13%) for an expansion in an SCA2 allele. In 20 families (53%), no expansions have been identified in any of the analyzed genes. Gaze palsy, spasticity, and hyperreflexia were significantly more common in SCA1, whereas slow saccades, hypotonia, hyporeflexia, and dystonia prevailed in SCA2 patients. Among the 16 families with an apparently recessive mode of ataxia inheritance, 4 (25%) were identified as having the FRDA mutation. Ataxia-causing mutations were identified in 8 (10.6%) of patients with apparently sporadic adult-onset ataxia.
A BS TRACT: Background: The objectives of this study were to investigate progressive cortical thi... more A BS TRACT: Background: The objectives of this study were to investigate progressive cortical thinning and volume loss in Parkinson's disease (PD) patients with different longitudinal patterns of cognitive decline: with stable normal cognition, with stable mild cognitive impairment, with conversion to mild cognitive impairment, and with conversion to dementia. Methods: We recruited 112 patients (37 Parkinson's disease with stable normal cognition, 20 Parkinson's disease with stable mild cognitive impairment, 36 Parkinson's disease with conversion to mild cognitive impairment, 19 Parkinson's disease with conversion to dementia) and 38 healthy controls. All patients underwent at least 2 visits within 4 years including clinical/cognitive assessments and structural MRI (total visits, 393). Baseline cortical thickness and gray matter volumetry were compared between groups. In PD, gray matter changes over time were investigated and compared between groups. Results: At baseline, compared with Parkinson's disease with stable normal cognition cases, Parkinson's disease with conversion to mild cognitive impairment patients showed cortical atrophy of the parietal and occipital lobes, similar to Parkinson's disease with stable mild cognitive impairment and Parkinson's disease with conversion to dementia patients. The latter groups (ie, patients with cognitive impairment from the study entry) showed additional involvement of the frontotemporal cortices. No baseline volumetric differences among groups were detected. The longitudinal analysis (group-by-time interaction) showed that, versus the other patient groups, Parkinson's disease with stable mild cognitive impairment and Parkinson's disease with conversion to dementia cases accumulated the least cortical damage, with Parkinson's disease with conversion to dementia showing unique progression of right thalamic and hippocampal volume loss; Parkinson's disease with conversion to mild cognitive impairment patients showing specific cortical thinning accumulation in the medial and superior frontal gyri, inferior temporal, precuneus, posterior cingulum, and supramarginal gyri bilaterally; and Parkinson's disease with stable normal cognition patients showing cortical thinning progression, mainly in the occipital and parietal regions bilaterally. Conclusions: Cortical thinning progression is more prominent in the initial stages of PD cognitive decline. The involvement of frontotemporoparietal regions, the hippocampus, and the thalamus is associated with conversion to a more severe stage of cognitive impairment. In PD, gray matter alterations of critical brain regions may be an MRI signature for the identification of patients at risk of developing dementia.
This study assesses the patterns of gray matter (GM) and white matter (WM) damage in patients wit... more This study assesses the patterns of gray matter (GM) and white matter (WM) damage in patients with Parkinson's disease and mild cognitive impairment (PD-MCI) compared with healthy controls and cognitively unimpaired PD patients (PD-Cu). Three-dimensional T1-weighted and diffusion tensor (DT) magnetic resonance imaging (MRI) scans were obtained from 43 PD patients and 33 healthy controls. Cognition was assessed using a neuropsychological battery. Tract-based spatial statistics was applied to compare DT MRI indices between groups on a voxel-by-voxel basis. Voxel-based morphometry was performed to assess GM atrophy. Thirty PD patients were classified as MCI. Compared with healthy controls, PD-Cu and PD-MCI patients did not have GM atrophy. No region of WM damage was found in PD-Cu patients when compared with healthy controls. Relative to healthy controls and PD-Cu patients, PD-MCI patients showed a distributed pattern of WM abnormalities in the anterior and superior corona radiata, genu, and body of the corpus callosum, and anterior inferior fronto-occipital, uncinate, and superior longitudinal fasciculi, bilaterally. Subtle cognitive decline in PD is associated with abnormalities of frontal and interhemispheric WM connections, and not with GM atrophy. DT MRI might contribute to the identification of structural changes in PD-MCI patients prior to the development of dementia.
This study aimed to identify functional neuroimaging patterns anticipating the clinical indicatio... more This study aimed to identify functional neuroimaging patterns anticipating the clinical indication for deep brain stimulation (DBS) in patients with Parkinson's disease (PD). A cohort of prospectively recruited patients with PD underwent neurological evaluations and resting-state functional MRI (RS-fMRI) at baseline and annually for 4 years. Patients were divided into two groups: 19 patients eligible for DBS over the follow-up and 41 patients who did not meet the criteria to undergo DBS. Patients selected as candidates for DBS did not undergo surgery at this stage. Sixty age-and sex-matched healthy controls performed baseline evaluations. Graph analysis and connectomics assessed global and local topological network properties and regional functional connectivity at baseline and at each time point. At baseline, network analysis showed a higher mean nodal strength, local efficiency, and clustering coefficient of the occipital areas in candidates for DBS over time relative to controls and patients not eligible for DBS. The occipital hyperconnectivity pattern was confirmed by regional analysis. At baseline, a decreased functional connectivity between basal ganglia and sensorimotor/frontal networks was found in candidates for DBS compared to patients not eligible for surgery. In the longitudinal analysis, patient candidate for DBS showed a progressively decreased topological brain organization and functional connectivity, mainly in the posterior brain networks, and a progressively increased connectivity of basal ganglia network compared to non-candidates for DBS. RS-fMRI may support the clinical indication to DBS and could be useful in predicting which patients would be eligible for DBS in the earlier stages of PD.
BackgroundEarly‐onset dementia (EOD) is conventionally considered to include patients with diseas... more BackgroundEarly‐onset dementia (EOD) is conventionally considered to include patients with disease onset before 65 years of age. Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) are two most common forms of degenerative EOD. Our aim was to screen for known gene mutation status in consecutive degenerative EOD patients.MethodTwo hundred and eight consecutive patients diagnosed according to the current clinical criteria for AD and FTD spectrum were recruited from the Neurology Clinic, Clinical Centre of Serbia from 01.04.2012. until 01.04.2017. Patient from AD spectrum were tested for APP, PSEN1, GRN, MAPT and C9ORF72 gene mutation and FTD patients for GRN, MAPT, C9ORF72, VCP, ANG gene mutation.ResultGene mutations were identified in 3.9% of our AD patients: 2.3% patients had mutations in the PSEN1 gene and 1.5% patients in the APP gene. There was no MAPT, GRN and C9ORF72 mutations carriers in our AD cohort. Genetic mutations have been demonstrated in 10.3% of patients with F...
BackgroundThe aim of the present study was to examine cognitive‐behavioral changes that may be re... more BackgroundThe aim of the present study was to examine cognitive‐behavioral changes that may be related to the lockdown and the quarantine during the COVID‐19 pandemic in Serbian patients with mild cognitive impairment (MCI), and Alzheimer dementia (AD). The caregivers’ distress was also evaluated.MethodThe 2089 registered patients with cognitive deficits, between December 2018 until January 2020 in Belgrade Memory clinic registry, University Clinical Center was contacted by telephone within the survey, 2 months after the lockdown declaration. Either the patients or their caregivers were asked to answer on: Caregiver Questionnaire, the Kingston Caregiver Stress Scale, Patient Questionnaire, Neuropsychiatric Questionnaire, and Clinical Dementia rating scale for caregiver and patients.ResultThe study included 1002 (females 56.%) patients either with AD (n = 389) or MCI (n = 604) who have got completed data set for analyses. Unfortunately, 74 patients died in the pandemic time, and 225 ...
This study investigated longitudinal clinical, structural and functional brain alterations in Par... more This study investigated longitudinal clinical, structural and functional brain alterations in Parkinson’s disease patients with freezing of gait (PD-FoG) and in those developing (PD-FoG-converters) and not developing FoG (PD-non-converters) over two years. Moreover, this study explored if any clinical and/or MRI metric predicts FoG development. Thirty PD-FoG, 11 PD-FoG-converters and 11 PD-non-converters were followed for two years. Thirty healthy controls were included at baseline. Participants underwent clinical and MRI visits. Cortical thickness, basal ganglia volumes and functional network graph metrics were evaluated at baseline and over time. In PD groups, correlations between baseline MRI and clinical worsening were tested. A ROC curve analysis investigated if baseline clinical and MRI measures, selected using a stepwise model procedure, could differentiate PD-FoG-converters from PD-non-converters. At baseline, PD-FoG patients had widespread cortical/subcortical atrophy, whil...
ABSTRACTBackgroundWhite matter hyperintensities (WMHs) have a role in cognitive impairment in nor... more ABSTRACTBackgroundWhite matter hyperintensities (WMHs) have a role in cognitive impairment in normal brain aging, while the effect on Parkinson's disease (PD) progression is still controversial.ObjectiveTo investigate the longitudinal evolution of micro‐ and macrostructural damage of cerebral white matter (WM) and its relationship with the clinical picture in PD.MethodsA total of 154 PD patients underwent clinical, cognitive, and magnetic resonance imaging (MRI) assessment once a year for up to 4 years. Sixty healthy controls underwent the same protocol at baseline. WMHs were identified and total WMH volume was measured. WMHs were also used as exclusion masks to define normal‐appearing white matter (NAWM). Using tract‐based spatial statistics, diffusion tensor (DT) MRI metrics of whole‐brain WM and NAWM were obtained. Linear mixed‐effects models defined the longitudinal evolution and association between variables. WM alterations were tested as risk factors of disease progression...
BackgroundTo investigate functional alterations in the cerebro‐cerebellar system in two Parkinson... more BackgroundTo investigate functional alterations in the cerebro‐cerebellar system in two Parkinson’s disease (PD) clinical phenotypes (tremor‐dominant [TD] and postural instability and gait disorder [PIGD]using stepwise functional connectivity (SFC).Method58 PD patients performed clinical and cognitive evaluations and resting‐state functional MRI (fMRI). PD cohort was divided into two groups: 32 patients with TD (PD‐TD) and 26 with PIGD (PD‐PIGD). 60 age‐ and sex‐matched healthy controls were also enrolled. SFC analysis aims to characterize regions that connect to specific seed brain areas at different levels of link‐step distances. The cerebellar seed‐region was identified using motor task‐based fMRI in 23 controls. For each of the SFC maps, whole‐brain two‐sample t‐test comparisons between groups were performed.ResultThe performance of the motor task during fMRI was associated with activation of the lobule VI and vermis of the cerebellum. SFC analysis at one‐link step distance show...
Objective: To investigate functional neural pathway organization and changes over-time in patient... more Objective: To investigate functional neural pathway organization and changes over-time in patients with Parkinson’s disease (PD) using advanced network-based techniques. Background: Graph theoretical analyses and network science are powerful tools to study functional organization of the brain. Design/Methods: 146 PD patients performed clinical and cognitive evaluations and resting-state functional MRI at baseline and every year for 4 years. Hierarchical cluster analysis identified two PD subtypes: 86 “early” and 60 “mild-to-severe” patients. Within the “early” subtype, two clinical groups were identified: “early-motor-predominant” and “early-diffuse”, the latter having greater cognitive deficits and more frequent non-motor manifestations. 60 age- and sex-matched controls performed baseline assessments. Graph analysis and connectomics assessed global and local topological network properties and regional functional connectivity (FC) at baseline and changes over-time. Results: “Early” ...
Objective.To detect the structural brain signatures of patients with a late age-of-onset major de... more Objective.To detect the structural brain signatures of patients with a late age-of-onset major depressive disorder (lo-MDD) relative to controls (training-dataset), and to test the ability of such measures to predict the presence of depression in Alzheimer’s disease (AD) and behavioral variant of frontotemporal dementia (bvFTD) (testing-dataset). Background.Whether depressive symptoms are intrinsic to neurodegeneration is still poorly understood. Lo-MDD may represent a model to understand the nature of depressive symptoms in AD and bvFTD. Methods.T1-weighted and diffusion tensor (DT)-MRI were obtained from 15 lo-MDD and 28 controls, and from an age-matched dataset of 61 AD and 27 bvFTD patients. Participants underwent a clinical assessment to detect the presence of depression. Cortical thickness (CT) and white matter (WM) metrics were obtained from all subjects, and compared among training-dataset groups to identify signatures of depression. MRI measures found to be significantly di...
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Papers by Elka Stefanova