Tanja Stojkovic

MRI measurements of brainstem structures in patients with Richardson's syndrome, progressive supranuclear palsy-parkinsonism, and Parkinson's disease†

We investigated the diagnostic accuracy of brainstem MRI measurements in patients with different progressive supranuclear palsy (PSP) syndromes and Parkinsons disease (PD). Using 3D T1‐weighted images, midbrain, and pons areas, as well as superior (SCP) and middle cerebellar peduncle (MCP) widths were measured in 10 patients with Richardsons syndrome (PSP‐RS), 10 patients with PSP‐parkinsonism (PSP‐P), 25 patients with PD, and 24 healthy controls. The ratio between pons and midbrain areas (pons/midbrain), that between MCP and SCP widths (MCP/SCP), and the MR parkinsonism index ([pons/midbrain]*[MCP/SCP]) were calculated. The pons/midbrain and the MR parkinsonism index allowed to differentiate PSP‐RS from PD with high sensitivity (90%, 100%), specificity (96%, 92%), and accuracy (94%, 97%). Only the pons/midbrain was found to distinguish PSP‐P from PD, but with a lower diagnostic accuracy (sensitivity = 60%, specificity = 96%, accuracy = 86%). Compared to PSP‐RS, PSP‐P experience a relatively less severe involvement of infratentorial brain. The pons/midbrain looks as a promising measure in the differentiation of individual PSP‐P from PD patients.

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.

Brain structural and functional connectivity in Parkinson's disease with freezing of gait

To use a multimodal approach to assess brain structural pathways and resting state (RS) functional connectivity abnormalities in patients with Parkinsons disease and freezing of gait (PD‐FoG).

Screening for Anxiety Symptoms in Parkinson Disease: A Cross-Sectional Study

Background: A limited number of studies examined anxiety in Parkinson disease (PD). Questionable validity of the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) defined anxiety disorders in PD population as well as a lack of validated rating scales hampered the investigation in this field. Objective: To screen for prevalence of anxiety symptoms and their associated demographic and clinical features in an outpatient-based cohort with PD. Patients and methods: A consecutive series of 360 patients with PD underwent investigation with the Hamilton Anxiety Rating Scale (HARS), the 17-item Hamilton Depression Rating Scale, Neuropsychiatric Inventory, section E (anxiety), motor scoring with Hoehn and Yahr staging, the Unified Parkinson’s Disease Rating Scale, and cognitive screening with the Mini-Mental State Examination. Results: In all, 136 (37.8%) patients with PD of our cohort had anxiety symptoms, whereas both depression and anxiety were recorded in 5.6% of the patients, while in 56.7% neither anxiety nor depression was present. Female gender, motor disability, and core depression symptoms were the main markers of anxiety in patients with PD. The severity of anxiety symptoms was not associated with asymmetry of motor symptoms. Education, disease duration, and levodopa dose were poor predictors in the model. The HARS had a satisfactory inter-item correlation, convergent validity, and factorial structure. Conclusions: Anxiety may be present as an isolated symptom, with specific demographic and clinical markers, and not only as a feature of depression in PD population. This highlighted the importance of identifying anxiety symptoms when treating patients with PD.

Structural Brain Connectome and Cognitive Impairment in Parkinson Disease

Purpose To investigate the structural brain connectome in patients with Parkinson disease (PD) and mild cognitive impairment (MCI) and in patients with PD without MCI. Materials and Methods This prospective study was approved by the local ethics committees, and written informed consent was obtained from all subjects prior to enrollment. The individual structural brain connectome of 170 patients with PD (54 with MCI, 116 without MCI) and 41 healthy control subjects was obtained by using deterministic diffusion-tensor tractography. A network-based statistic was used to assess structural connectivity differences among groups. Results Patients with PD and MCI had global network alterations when compared with both control subjects and patients with PD without MCI (range, P = .004 to P = .048). Relative to control subjects, patients with PD and MCI had a large basal ganglia and frontoparietal network with decreased fractional anisotropy (FA) in the right hemisphere and a subnetwork with increased mean diffusivity (MD) involving similar regions bilaterally (P < .01). When compared with patients with PD without MCI, those with PD and MCI had a network with decreased FA, including basal ganglia and frontotemporoparietal regions bilaterally (P < .05). Similar findings were obtained by adjusting for motor disability (P < .05, permutation-corrected P = .06). At P < .01, patients with PD and MCI did not show network alterations relative to patients with PD without MCI. Network FA and MD values were used to differentiate patients with PD and MCI from healthy control subjects and patients with PD without MCI with fair to good accuracy (cross-validated area under the receiver operating characteristic curve [principal + secondary connected components] range, 0.75-0.85). Conclusion A disruption of structural connections between brain areas forming a network contributes to determine an altered information integration and organization and thus cognitive deficits in patients with PD. These results provide novel information concerning the structural substrates of MCI in patients with PD and may offer markers that can be used to differentiate between patients with PD and MCI and patients with PD without MCI.

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.

Multiparametric MRI to distinguish early onset Alzheimer's disease and behavioural variant of frontotemporal dementia

This prospective study explored whether an approach combining structural [cortical thickness and white matter (WM) microstructure] and resting state functional MRI can aid differentiation between 62 early onset Alzheimers disease (EOAD) and 27 behavioural variant of frontotemporal dementia (bvFTD) patients. Random forest and receiver operator characteristic curve analyses assessed the ability of MRI in classifying the two clinical syndromes. All patients showed a distributed pattern of brain alterations relative to controls. Compared to bvFTD, EOAD patients showed bilateral inferior parietal cortical thinning and decreased default mode network functional connectivity. Compared to EOAD, bvFTD patients showed bilateral orbitofrontal and temporal cortical thinning, and WM damage of the corpus callosum, bilateral uncinate fasciculus, and left superior longitudinal fasciculus. Random forest analysis revealed that left inferior parietal cortical thickness (accuracy 0.78, specificity 0.76, sensitivity 0.83) and WM integrity of the right uncinate fasciculus (accuracy 0.81, specificity 0.96, sensitivity 0.43) were the best predictors of clinical diagnosis. The combination of cortical thickness and DT MRI measures was able to distinguish patients with EOAD and bvFTD with accuracy 0.82, specificity 0.76, and sensitivity 0.96. The diagnostic ability of MRI models was confirmed in a subsample of patients with biomarker-based clinical diagnosis. Multiparametric MRI is useful to identify brain alterations which are specific to EOAD and bvFTD. A severe cortical involvement is suggestive of EOAD, while a prominent WM damage is indicative of bvFTD.

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

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

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

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