Aleksandra Tomić

Mild cognitive impairment in Parkinson's disease is associated with a distributed pattern of brain white matter damage

This study assesses the patterns of gray matter (GM) and white matter (WM) damage in patients with Parkinsons 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. Hum Brain Mapp 35:1921–1929, 2014.

The topography of brain damage at different stages of Parkinson's disease.

This study investigated gray matter (GM) and white matter (WM) damage in 89 patients at different clinical stages of Parkinsons disease (PD) (17 early, 46 mild, 14 moderate, and 12 severe) to differentiate the trajectories of tissue injury in this condition. PD patients had a very little GM atrophy even at the more advanced stages of the disease. Microstructural damage to the WM occurs with increasing PD severity and involves the brainstem, thalamocortical pathways, olfactory tracts, as well as the major interhemispheric, limbic, and extramotor association tracts. The most marked WM damage was found in moderate vs. mild cases. WM damage correlated with the degree of global cognitive deficits. WM abnormalities beyond the nigrostriatal system accumulate with increasing PD severity. WM damage is likely to contribute to the more severe motor and nonmotor dysfunctions occurring in patients at the later stages. Hum Brain Mapp 34:2798–2807, 2013.

Suicide and suicidal ideation in Parkinson's disease

Little is known about the prevalence and correlates of suicidal behavior in Parkinsons disease (PD). In the first part of the study, we followed a cohort of 102 consecutive PD patients for 8 years and found that the suicide-specific mortality was 5.3 (95% CI 2.1-12.7) times higher than expected. In the second part, we tested 128 PD patients for death and suicidal ideation and administered an extensive neurological, neuropsychological and psychiatric battery. Current death and/or suicidal ideation was registered in 22.7%. On univariate logistic regression analysis, psychiatric symptoms (depression, but also anxiety and hopelessness), but not the PD-related variables, were associated with such ideation. On multivariate logistic regression analysis this association held for major depression (odds ratio=4.6; 95% CI 2.2-9.4; p<0.001), psychosis (odds ratio=19.2; 95% CI 1.4-27.3; p=0.026), and increasing score of the Beck Hopelessness Scale (odds ratio=1.2; 95% CI 1.0-1.4; p=0.008). In conclusion, the suicide risk in PD may not be as high as it is expected, but it is certainly not trivial. According to our data almost a quarter of PD patients had death and/or suicidal ideation, that may significantly influence their quality of life.

Neuropsychiatric aspects of treated Wilson's disease ☆

The objective of the current cross-sectional study was to use standardized psychiatric interviews (the Structured Clinical Interview for DSM-IV Axis I Disorders and the Neuropsychiatric Inventory; NPI) in order to better characterize psychiatric symptoms in 50 consecutive, treated and clinically stable patients with Wilsons disease (WD). Nine patients (18%) had one, 7 patients (14%) had two, and 20 (40%) had >or= 3 neuropsychiatric symptoms present. The most often endosed symptoms were anxiety (62%), depression (36%), irritability (26%), as well as disinhibition and apathy (24% each). Twenty two patients (44%) had a score >or= 4 on at least one of the NPI items: again, most frequently anxiety (17 patients; 34%), depression (13 patients; 26%) and apathy (9 patients; 18%). Therefore, even among stable, long-term treated patients with WD approximately 70% experienced psychiatric symptoms.

Clinical, cognitive, and behavioural correlates of white matter damage in progressive supranuclear palsy

White matter (WM) tract alterations were assessed in patients with progressive supranuclear palsy (PSP) relative to healthy controls and patients with idiopathic Parkinson’s disease (PD) to explore the relationship of WM tract damage with clinical disease severity, performance on cognitive tests, and apathy. 37 PSP patients, 41 PD patients, and 34 healthy controls underwent an MRI scan and clinical testing to evaluate physical disability, cognitive impairment, and apathy. In PSP, the contribution of WM tract damage to global disease severity and cognitive and behavioural disturbances was assessed using Random Forest analysis. Relative to controls, PSP patients showed diffusion tensor (DT) MRI abnormalities of the corpus callosum, superior cerebellar peduncle (SCP), cingulum and uncinate fasciculus bilaterally, and right inferior longitudinal fasciculus. Corpus callosum and SCP DT MRI measures distinguished PSP from PD patients with high accuracy (area under the curve ranging from 0.89 to 0.72). In PSP, DT MRI metrics of the corpus callosum and superior cerebellar peduncles were the best predictors of global disease severity scale scores. DT MRI metrics of the corpus callosum, right superior longitudinal and inferior longitudinal fasciculus, and left uncinate were the best predictors of executive dysfunction. In PSP, apathy severity was related to the damage to the corpus callosum, right superior longitudinal, and uncinate fasciculi. In conclusion, WM tract damage contributes to the motor, cognitive, and behavioural deficits in PSP. DT MRI offers markers for PSP diagnosis, assessment, and monitoring.

Diffusion tensor MRI contributes to differentiate Richardson's syndrome from PSP-parkinsonism

This study investigated the regional distribution of white matter (WM) damage in Richardsons syndrome (PSP-RS) and progressive supranuclear palsy-Parkinsonism (PSP-P) using diffusion tensor (DT) magnetic resonance imaging (MRI). The DT MRI classificatory ability in diagnosing progressive supranuclear palsy (PSP) syndromes, when used in combination with infratentorial volumetry, was also quantified. In 37 PSP (21 PSP-RS, 16 PSP-P) and 42 controls, the program Tract-Based Spatial Statistics (TBSS; www.fmrib.ox.ac.uk/fsl/tbss) was applied. DT MRI metrics were derived from supratentorial, thalamic, and infratentorial tracts. The magnetic resonance parkinsonism index (MRPI) was calculated. All PSP harbored diffusivity abnormalities in the corpus callosum, frontoparietal, and frontotemporo-occipital tracts. Infratentorial WM and thalamic radiations were severely affected in PSP-RS and relatively spared in PSP-P. When MRPI and DT MRI measures were combined, the discriminatory power increased for each comparison. Distinct patterns of WM alterations occur in PSP-RS and PSP-P. Adding DT MRI measures to MRPI improves the diagnostic accuracy in differentiating each PSP syndrome from healthy individuals and each other.

Circumstances of falls and fall-related injuries among patients with Parkinson's disease in an outpatient setting

Falls represent continuing, disabling and costly problem in Parkinsons disease (PD). The study was carried out at the Neurology Clinic in Belgrade from August 2011 to December 2012. As many as 180 community dwelling persons with PD aged 22-83 years who sustained a fall in past 6 months were included. Characteristics of the most recent fall were obtained through detailed interviews. Inclusion criteria were: Mini Mental State Examination (MMSE)≥24, ability to walk independently for at least 10 m and ability to statically stand for at least 90 s. Exclusion criteria were: presence of other neurologic as well as psychiatric, visual, audio-vestibular and orthopedic impairments. Falls more frequently took place outside (57.2%) and in the morning (53.9%). As much as 38.9% of persons with PD sustained an injury. Soft-tissue contusion was the most common injury (71.8%) both after indoor and outdoor falls. Fractures accounted for 5% of all fall-related injuries. All the fractures were either arm, clavicle or rib fractures. Tripping was identified as risk factor for outdoor falls (OR=7.90; 95% confidence interval [95% CI] 3.21-19.39; p=0.001). In contrast, lower extremity weakness (OR=0.20; 95% CI 0.05-0.72; p=0.015) and internal sense of sudden loss of balance (OR=0.19; 95% CI 0.05-0.73; p=0.015) were risk factors for indoor falls. To accomplish long-term results, development of particular prevention programs for persons with PD who fall at home vs. outdoors is recommended.

Transcranial sonography in Wilson's disease

Transcranial sonography (TCS) has been recently recognized as a reliable and sensitive tool in detecting basal ganglia (BG) abnormalities in several movement disorders, where different patterned hyperechogenic lesions were demonstrated. The aim of this study was to investigate changes in TCS in a larger group of clinically stable patients with Wilsons disease (WD), and to correlate them with demographic and clinical data. TCS was conducted in 54 consecutive, clinically stable patients with WD who were classified as predominantly neurologic or hepatic form of the disease and were adequately assessable by TCS from both sides. TCS revealed significantly higher prevalence of SN (p = 0.007) and LN hyperechogenicity (0.001) in WD patients when compared to controls. Moderate to marked SN hyperechogenicity was found in 31.5% of WD patients (in 42% and 7% of those with neurologic and hepatic form of WD, respectively) and in 8% of healthy controls. Disease severity correlated with the hyperechogenicity of SN (r = 0.303; p = 0.029) and with the width of the third ventricle (r = 0.351; p = 0.011). There is only one report of TCS in WD previous to our study. Both studies proved the ability of TCS to detect accumulation of copper and probably other trace metals, such as iron and manganese, in the BG of WD patients.

Mild Cognitive Impairment in Early Parkinson's Disease Using the Movement Disorder Society Task Force Criteria: Cross-Sectional Study in Hoehn and Yahr Stage 1

Background: Mild cognitive impairment (MCI) in Parkinsons disease (PD) is common and confers a higher risk for developing dementia. Methods: In this cross-sectional study of MCI in PD conducted at a university hospital, a comprehensive neuropsychological battery covering five domains (attention/working memory, executive, verbal, and visual memory, language, and visuospatial) was administered to 111 nondemented PD patients in Hoehn and Yahr stage 1 and to 105 healthy matched control subjects (HC). MCI was diagnosed according to level 2 of the Movement Disorder Society Task Force criteria. Results: Criteria for MCI associated with PD (PD-MCI) were fulfilled by 24% of PD patients in the initial stage of the disease at the z cutoff scores of -1.5 SD in contrast to 7% of HC fulfilling criteria for MCI. Memory and visuospatial domains were the most commonly affected at -1.5 SD. PD-MCI patients mostly had a multiple-domain MCI subtype (78%). They presented a more severe bradykinesia and higher mood and apathy scores in comparison with cognitively normal PD patients. Basic motor scores predicted performance on some cognitive tests and specific cognitive-motor relationships emerged. Conclusions: MCI, predominantly of a multiple-domain subtype, was quite prevalent even in the initial stage of PD.

Phenotype of non-c.907_909delGAG mutations in TOR1A: DYT1 dystonia revisited.

BACKGROUND In addition to the most frequent TOR1A/DYT1 mutation (c.907_909delGAG), a growing number of TOR1A sequence variants are found in dystonia patients. For most, functional characterization has demonstrated pathogenicity at different levels, implying that TOR1A genetic testing should not be limited to screening for c.907_909delGAG. METHODS We tested 461 Serbian patients with isolated or combined dystonia for changes in the TOR1A gene and performed a systematic literature review of the clinical characteristics of patients carrying TOR1A mutations other than c.907_909delGAG. RESULTS One likely pathogenic TOR1A mutation (c.385G>A, p.Val129Ile) was detected in an adult-onset cervical dystonia patient. This change is in proximity to the previously reported p.Glu121Lys mutation and predicted to decrease the stability of TOR1A-encoded protein TorsinA. CONCLUSIONS Our patient and three other reported carriers of non-c.907_909delGAG-mutations within the first three exons of TOR1A showed similar phenotypes of adult-onset focal or segmental cervical dystonia. This observation raises the possibility of genotype-phenotype correlations in DYT1 and indicates that the clinical spectrum of this type of dystonia might be broader then previous classic descriptions.