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Background: The hypothesis that the effectiveness of deep brain stimulation (DBS) in Parkinson's disease (PD) would be related to connectivity dysfunctions between the site of stimulation and other brain regions is growing. Objective: To investigate how the subthalamic nucleus (STN), the most frequently used DBS target for PD, is functionally linked to other brain regions in PD patients according to DBS eligibility. Methods: Clinical data and resting-state functional MRI were acquired from 60 PD patients and 60 age- and sex-matched healthy subjects within an ongoing longitudinal project. PD patients were divided into 19 patients eligible for DBS and 41 non-candidates. Bilateral STN were selected as regions of interest and a seed-based functional MRI connectivity analysis was performed. Results: A decreased functional connectivity between STN and sensorimotor cortex in both PD patient groups compared to controls was found. Whereas an increased functional connectivity between STN and thalamus was found in PD patient groups relative to controls. Candidates for DBS showed a decreased functional connectivity between bilateral STN and bilateral sensorimotor areas relative to non-candidates. In patients eligible for DBS, a weaker STN functional connectivity with left supramarginal and angular gyri was related with a more severe rigidity and bradykinesia whereas a higher connectivity between STN and cerebellum/pons was related to poorer tremor score. Conclusion: Our results suggest that functional connectivity of STN varies among PD patients eligible or not for DBS. Future studies would confirm whether DBS modulates and restores functional connectivity between STN and sensorimotor areas in treated patients. [ABSTRACT FROM AUTHOR]

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. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Introduction: Psychosis and agitation represent a major therapeutic problem in young onset Alzheimer's disease (YOAD), given that these symptoms pose a great risk to the patient, but treatment options are limited. Anti‐psychotic use is connected to different side effects, but increased mortality noted in older demented population is particularly worrying. Since YOAD patients are younger we wanted to examine if anti‐psychotic use is connected to decreased survival in these patients as well. Aim: To examine the association between the use of anti‐psychotics and the length of survival in YOAD. Material and methods: This is a retrospective study on 135 patients from Memory Center of Neurology Clinic, Clinical Center of Serbia, with clinical diagnosis of YOAD. We included outpatients that had first visit to our clinic from 01.04.2012. do 01.04.2017. The need to introduce anti‐psychotics was noted during the follow‐up period and the difference in the survival of patients who at some point during the observation (from inclusion in the register until 2019) received anti‐psychotic therapy and those who did not. In this analysis we used Kaplan Meier survival analysis with log rank test with the time from the onset of symptoms to the outcome as an independent variable. Outcome was survived/died (at 2019.) and dependent variable was whether or not the patient received anti‐psychotics. Results: During the period covered by this analysis, ending in 2019, among patients who received anti‐psychotics, 42 patients died while 20 remained alive. In patients who did not receive anti‐psychotics, 47 patients died while 26 remained alive. There was no statistically significant difference between the number of deaths in the group of patients who were and were not treated with anti‐psychotics (p = 0.682). Kaplan Meier analysis showed that the use of anti‐psychotics (at any point during observation) did not significantly affected survival measured as the time elapsed from the onset of symptoms to the outcome (death or 2019). Conclusion: The use of anti‐psychotics in patients with YOAD is not associated with reduced lifespan. [ABSTRACT FROM AUTHOR]

Introduction: Specific feature of young onset Alzheimer's disease (YOAD) patients is that their diagnosis and therefore their treatment is usually delayed. Firstly, they present atypically, secondly, they have a higher cognitive reserve and symptoms are later recognized and finally at that age, the family, and the patients themselves, do not think about the possibility of dementia, which prolongs the time period to seeking medical help (on average 2‐3 years). Aim: To examine the association of survival in YOAD with time elapsed from the onset of symptoms to the initiation of pharmacotherapy. Material and methods: This is a retrospective study on 135 patients from Memory Center of Neurology Clinic, Clinical Center of Serbia, with clinical diagnosis of YOAD. We included outpatients that had first visit to our clinic from 01.04.2012. do 01.04.2017. The association of survival with time elapsed from onset of symptoms to initiation of therapy was examined by Kaplan Meier survival analysis with log rank test. Results: From 2012, when the registry was created, till 2019, 89 out of 135 included patients died. Kaplan Meier survival analysis showed that patients with lower MMSE score (from 15 points and below) and who could not dress themselves or perform personal hygiene at the time of inclusion in our registry have a shorter expected survival than those who had MMSE 16 and above (p = 0.019) and who functioned independently in terms of these activities of daily living (p = 0.041 for dressing and p = 0.018 for performing personal hygiene). Patients in whom the introduction of therapy was delayed 3 or less years survived for a year longer than patients in whom therapy was introduced 4 or more years after the onset of dementia symptoms (p = 0.004). Conclusion: Our study clearly showed that certain clinical parameters (degree of cognitive and functional damage at the time of therapy introduction), but also delay in introducing therapy from symptoms onset determine the length of survival in YOAD. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) occur frequently in patients with young onset Alzheimer's Disease (YOAD). However, studies on psychotropic drug use (PDU) mainly focus on elderly patients with dementia. It is important to know the prevalence of PDU in patients with YOAD in order to reduce excess use of these medications in this group. Our study aim is to investigate the frequency of PDU among patients with YOAD. Method: This is a retrospective study on 135 patientsfrom Memory Centre of Neurology Clinic, Clinical Centre of Serbia, with clinical diagnosis of YOAD. We included outpatients that had first visit to our clinic from 01.04.2012. to 01.04.2017. The data on psychotropic drug use werecollected from medical records. Statistical analyses were done using SPSS20. Result: Mean age of our patients at inclusion was 60.07±5.27 and mean disease duration was 3.42±1.53. 85.18% patients received PT drugs. Antidepressants were prescribed most frequently, in 63.7% of patients, while antipsychotics were used by 45.93% of patients, and benzodiazepines by 61.5%. The earliest prescribed PTs were antidepressants, 3.66 years from the first symptoms and 1.45 years after diagnosis and antidepressants were used the longest in our group, 3.15 years. Conclusion: The frequency pf PDU in our cohort is high and comes close to PDU in patients in nursing homes in other European countries. The reason might be the high frequency of NPS in YOAD but also prescribing practice in the absence of systematic non pharmacological measures and that is something we have to take notice of. [ABSTRACT FROM AUTHOR]

Background: Early‐onset dementia (EOD) is conventionally considered to include patients with disease onset before 65 years of age, with Alzheimer's disease (AD) being the most common form of EOD. Our aim was to investigate the clinical correlates of psychotropic therapy use in early onset AD (EOAD). Method: This observational retrospective study included 135 consecutive EOAD patients who were diagnosed according to current criteria from April 1, 2012. until April 1, 2017. year at the Neurology Clinic, University Clinical Centre of Serbia. Neuropsychiatric symptoms were assessed using Neuropsychiatric inventory, Hamilton scale for depression and anxiety, and apathy scale. Result: The frequency of psychotropic therapy use in our EOAD group was high with 85.18% patients receiving these drugs. Patients often received combinations of psychotropic drugs, 40% of patients received two psychotropic drugs (the most common was a combination of antidepressants and benzodiazepines). Clinical correlates of benzodiazepine administration in our group were agitation, irritability and anxiety. Antipsychotics use correlated with hallucinations, anxiety, irritability and sleep disorders. Psychotropic therapy was not associated with faster cognitive deterioration in EOAD patients, while more frequent functional deterioration correlated with the use of antipsychotics. The use of antipsychotics in patients with EOAD was not associated with serious side effects and reduced life expectancy. Conclusion: The frequency of psychotropic therapy use in our EOAD group was high. Psychotropic therapy was not associated with faster cognitive deterioration, serious side effects and reduced life expectancy in our EOAD patients. [ABSTRACT FROM AUTHOR]

Background: Myotonic Dystrophy Type 1 (MD1) is a neuromuscular disease in which subtle behavioral disturbance is often described. Few studies evaluated frontal lobe function and behavioral scales in relation with brain pathology. Method: 27 MD1 adult patients (mean age 46), were included. All patients performed an exhaustive neuropsychological assessment with a specific focus on cognitive and behavioral frontal functions. 18 MD1 patients and 18 healthy controls had a brain MRI with T1 and T2 Flair sequences. We performed a voxel‐based analysis with SPM12 via Clinica Software. The normalized data were smoothed with an isotropic Gaussian kernel of 8 mm. Statistical analysis was performed using general linear model with age sex and total intra cranial volume as covariates. Statistics were corrected for multiple comparisons with family‐wise error (FWE) correction at the cluster level with a height threshold of 0.001. T2 white matter lesions were segmented with VolBrain software. Result: More than 60 % of the patients showed significant impairment in executive frontal functions (inhibition, mental flexibility, contextualization and theory of mind) with relative sparing of motivation, emotion recognition and initiation/planification. MD1 patients MRI compared to healthy controls showed grey matter atrophy in medial temporal lobe, (parahippocampus mostly) and in a smaller extent in the middle frontal gyrus and the right caudate nucleus and excessive white matter hyperintensities, mostly in temporal lobes. Frontal cognitive and behavioral impairment on neuropsychological testing was correlated with medial temporal and in a smaller extent frontal localization. Conclusion: Behavioral disturbance in MD1 might be related to cognitive impairment in mental flexibility and contextualization rather than a specific social cognition deficit. This impairment might be related to white matter lesions or grey matter disease (including frontal‐subcortical network or parahippocampus, known to apprehend contextualization in emotion detection). Altogether, these findings confirm the hypothesis of a specific central nervous system involvement in MD1 patients. [ABSTRACT FROM AUTHOR]

Our objective was to determine whether the presence of executive dysfunction in non-demented amyotrophic lateral sclerosis (ALS) patients might affect the longevity of survival. Forty-eight consecutive non-demented ALS patients (mean age = 52.93 ± 12.37) were followed for five years. All patients underwent clinical and neuropsychological assessments at baseline visit. Further, a yearly follow-up check for associated dementia (ALS-Dem) was completed and the time of death was recorded, when applicable. Executive deficits were shown in 49.5% of ALS patients, with the most striking differences found on the tests of verbal fluency (both phonemic and category,p < 0.01); as well as inefficient strategy on a working memory test (p < 0.05); as on the more demanding levels of the planning and problem solving task (p < 0.01). It appears that the baseline executive status might predict survival in ALS (p = 0.075), and the patients presenting executive dysfunction could have up to three times greater risk of death, after adjustment by several potential confounding factors. In conclusion, this study suggests that executive dysfunction could potentially influence survival in ALS patients. The cognitive testing might give us important clues about the prognosis of the disease. Further studies with larger sample size are necessary. [ABSTRACT FROM PUBLISHER]

Background: The 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. Method: The 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. Result: The 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 subjects rejected to participate, and the rest were not reached due to wrong phone number, or missed contact record. Caregivers reported a worsening in cognitive functions in 55.1% of AD patients, and increased neuropsychiatric symptoms were reported in 59.8% as worsening of preexisting symptoms (41.9%) or as new onset (21%). The most common were depression, apathy, sleep disorders and anxiety. The prevalence of these symptoms was the same as before the pandemic, but there was a change in their frequency and intensity. Approximately 15.9% of patients with MCI showed the onset of new behavioral symptoms, sleep disorder and anxiety were the predominant new symptoms. The transition from MCI to dementia was recorded in 24%. Due to increased patients' neuropsychiatric burden stress‐related symptoms were experienced by two‐thirds of caregivers. Conclusion: Pandemic quarantine induces a significant increase of neuropsychiatric symptoms in approximately half of patients and stress‐related symptoms in two‐thirds of caregivers. Health services need to plan a post‐pandemic strategy in order to address these emerging needs. [ABSTRACT FROM AUTHOR]

Objective: To use a multimodal approach to assess brain structural pathways and resting state (RS) functional connectivity abnormalities in patients with Parkinson's disease and freezing of gait (PD-FoG). Methods: T1-weighted, diffusion tensor (DT) MRI and RS functional MRI (fMRI) were obtained from 22 PD-FoG patients and 35 controls on a 3.0 T MR scanner. Patients underwent clinical, motor, and neuropsychological evaluations. Gray matter (GM) volumes and white matter (WM) damage were assessed using voxel based morphometry and tract-based spatial statistics, respectively. The pedunculopontine tract (PPT) was studied using tractography. RS fMRI data were analyzed using a model free approach investigating the main sensorimotor and cognitive brain networks. Multiple regression models were performed to assess the relationships between structural, functional, and clinical/cognitive variables. Analysis of GM and WM structural abnormalities was replicated in an independent sample including 28 PD-FoG patients, 25 PD patients without FoG, and 30 healthy controls who performed MRI scans on a 1.5 T scanner. Results: Compared with controls, no GM atrophy was found in PD-FoG cases. PD-FoG patients showed WM damage of the PPT, corpus callosum, corticospinal tract, cingulum, superior longitudinal fasciculus, and WM underneath the primary motor, premotor, prefrontal, orbitofrontal, and inferior parietal cortices, bilaterally. In PD-FoG, right PTT damage was associated with a greater disease severity. Analysis on the independent PD sample showed similar findings in PD-FoG patients relative to controls as well as WM damage of the genu and body of the corpus callosum and right parietal WM in PD-FoG relative to PD no-FoG patients. RS fMRI analysis showed that PD-FoG is associated with a decreased functional connectivity of the primary motor cortex and supplementary motor area bilaterally in the sensorimotor network, frontoparietal regions in the default mode network, and occipital cortex in the visual associative network. Conclusions: This study suggests that FoG in PD can be the result of a poor structural and functional integration between motor and extramotor (cognitive) neural systems. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia (EOD), characterized by behavioral changes (behavioral variant; bvFTD) or language deficits. A hexanucleotide repeat expansion in a noncoding region of chromosome 9 open reading frame 72 (C9orf72) has been proved to be a major cause of both familial and sporadic amyotrophic lateral sclerosis or FTD, with or without concomitant motor neuron disease (MND). Methods: The aim of this study was to assess the frequency of the C9orf72 hexanucleotide expansion in a cohort of 117 Serbian patients with EOD and to report phenotypic features of identified carriers. Results: We identified 4 of 117 (3.4%) patients with EOD to have C9orf72 hexanucleotide expansions. All patients were classified in the FTD disease spectrum group (8.2%): 3 patients fulfilled the criteria for bvFTD, and 1 patient had FTD-MND. None of the patients with the C9orf72 hexanucleotide expansion fulfilled the diagnostic criteria for language variants of FTD, FTD-progressive supranuclear palsy overlap syndrome, dementia with Lewy bodies or Alzheimer's dementia. Conclusion: In a cohort of consecutive patients with EOD, 3.4% had the C9orf72 hexanucleotide expansion with clinical phenotypes of bvFTD or an overlap of bvFTD and MND. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Having in mind a significant percentage of atypical presentations at disease onset (behavioral symptoms, depression, psychotic symptoms or non‐cognitive cognitive deficits), understanding clinical heterogeneity of early onset Alzheimer's disease (EOAD) and frontotemporal dementia (EOFTD) can improve early diagnosis and differentiation between these clinical entities. Our objective was to investigate the heterogeneity of neuropsychiatric symptoms (NPS) in EOAD and EOFTD spectrum. Method: Two hundred and seven consecutive patients with EOAD and EOFTD spectrum, diagnosed according to the current clinical criteria, were recruited from the Neurology Clinic, Clinical Centre of Serbia. Sociodemographic and clinical characteristics were evaluated using a pre‐designed semi‐structured questionnaire while neuropsychiatric symptoms (NPS) were evaluated using Neuropsychiatric Inventory (NPI). Result: EOAD and EOFTD patients did not differ in age, age at disease onset, duration of the disease, gender and education. In comparison to EOAD, patients in the EOFTD spectrum expressed agitation, euphoria, apathy, disinhibition, irritability, aberrant motor behavior and dietary changes more frequently. EOFTD behavioral variant patients expressed apathy, aberrant motor behavior and disinhibition more often than patients with PPA, while in PPA anxiety was represented. In EOAD group total NPI score correlated with clinical dementia rating scale score. In the advanced stages of dementia, EOAD patients expressed agitation and irritability more frequently than at disease onset, while in advanced EOFTD agitation and aberrant motor behavior were more frequent than in the earlier stages of the disease. Amnestic and non‐amnestic presentation of EOAD did not differ in frequency on NPS Conclusion: NPS are a hallmark of behavioral variant of EOFTD and later stages of EOAD. [ABSTRACT FROM AUTHOR]

Background: Early‐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. Method: Two 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. Result: Gene 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 FTD. The most frequent was the hexanucleotide expansion in C9ORF72 (6.4% of all FTD patients), following mutations in GRN, VCP and ANG with the same frequency of (1.3% FTD for each gene). No patient was a MAPT mutation carrier. Conclusion: Gene mutations were rare causes in our AD cohort. The frequency of carriers was higher in FTD patients‐ mutations were identified in C9ORF72, GRN, VCP and ANG genes. No MAPT mutation carriers were identified in our cohort of patients with degenerative EOD. [ABSTRACT FROM AUTHOR]