Franziska Maier

Parkinson Subtypes Progress Differently in Clinical Course and Imaging Pattern

Objective To elucidate whether Parkinson’s disease (PD) subtypes show a differential pattern of FP-CIT-SPECT binding during the disease course. Methods We examined 27 patients (10 female, 17 male, mean age 61.68±11.24 years, 14 tremordominant, 13 akinetic-rigid) with [123I]FP-CIT-SPECT and clinical ratings including UPDRS III after at baseline and after a mean period of 2.47 years. Patients had been classified at baseline as tremordominant or akinetic-rigid according to a “tremor score” and “non-tremor score”. These subgroups were compared for differences in disease progression. Means of clinical ratings and the quantitative analyses of FP-CIT-SPECT for ipsi- and contralateral putamen and caudate nucleus were calculated and compared between baseline and follow-up. Results There were no statistical differences concerning age, disease duration, L-Dopa equivalent dose, disease severity (UPDRS III) or dopaminergic uptake in FP-CIT-SPECT at baseline between both subgroups. At follow-up, akinetic-rigid patients showed a distinct and statistically significant reduction of the dopaminergic uptake associated with significant progression of the clinical symptoms (UPDRS III). In contrast, in tremor patients the aggravation of clinical symptoms and dopaminergic deficit was less pronounced without statistical significance among assessments. Conclusions This study shows for the first time a considerable progression of clinical symptoms and in-vivo dopaminergic deficit of akinetic-rigid compared to tremordominant PD patients over time. Our data may help to improve strategic planning of further therapeutic trials and to provide a clearer prognosis for patients regarding the perspective of their disease.

Patients’ expectations of deep brain stimulation, and subjective perceived outcome related to clinical measures in Parkinson's disease: a mixed-method approach

Objective To study patients’ expectations of subthalamic deep brain stimulation (STN-DBS) and their subjective perceived outcome, by using qualitative and quantitative methods in Parkinsons disease (PD). Methods PD patients were prospectively examined before and 3 months after surgery. Semistructured interviews regarding preoperative expectations and postsurgical subjective perceived outcome were conducted. These were analysed using content analysis. For statistical analyses, patients were classified according to their subjective perceived outcome, resulting in three different subjective outcome groups (negative, mixed, positive outcome). The groups were used for multiple comparisons between and within each group regarding motor impairment, quality of life (QoL), neuropsychiatric status and cognitive functioning, using standard instruments. A logistic regression analysis was conducted to find predictors of subjective negative outcome. Receiver operating characteristic curves were used to analyse cut-off scores for predictive tests. Results Of the 30 PD patients participating, 8 had a subjective negative outcome, 8 a mixed and 14 a positive outcome. All groups significantly improved in motor functioning. Patients with subjective negative outcome were characterised by preoperative unrealistic expectations, no postsurgical improvement in QoL, and significantly higher presurgical and postsurgical apathy and depression scores. Higher preoperative apathy and depression scores were significant predictors of negative subjective outcome. Cut-off scores for apathy and depression were identified. Conclusions The mixed-method approach proved useful in examining a patients subjective perception of STN-DBS outcome. Our results show that significant motor improvement does not necessarily lead to a positive subjective outcome. Moreover, PD patients should be screened carefully before surgery regarding apathy and depression. (DRKS-ID: DRKS00003221).

Impaired self-awareness of motor deficits in Parkinson's disease: association with motor asymmetry and motor phenotypes.

This study investigated impaired self‐awareness of motor deficits in nondemented, nondepressed Parkinsons disease (PD) patients during a defined clinical on state.

Hypomania and mania related to dopamine replacement therapy in Parkinson's disease.

OBJECTIVES To investigate hypomania and mania related to dopamine replacement therapy (DRT) in Parkinsons disease (PD). METHODS We recruited 108 non-demented PD patients without deep brain stimulation from a movement disorders in and outpatient clinic. Forty-five age- and gender-matched controls were also included. Disease characteristics, cognitive functioning, comorbid psychiatric diseases, dopaminergic and psychiatric medication were evaluated. Diagnosis of DRT-related hypomania and mania was based on DSM-IV-TR criteria with supplementary assessment of two mania self-rating scales. First, patients and controls were compared. Patients with DRT-related hypomania or mania were then compared to the remaining patients. A binary logistic regression analysis was performed to identify correlates of DRT-related hypomania. RESULTS Patients scored significantly higher on mania self-rating scales than controls. Twelve patients (11.1%) had DRT-related hypomania and six patients (5.6%) had DRT-related mania. Both groups had significantly higher self-rating mania-scores than patients without these mood states. DRT-related hypomania was significantly related to younger age, younger age at PD onset, dyskinesias, higher levodopa equivalent daily dose, dopamine dysregulation, and amantadine treatment. In contrast, DRT-related mania was significantly associated with hallucinations and delusions, history of levodopa-induced psychosis, quetiapine treatment, higher depression and daily levodopa dose, and cognitive deficits. Regression analysis revealed dopamine dysregulation, dyskinesias, amantadine treatment, and younger age at PD onset as significant correlates of DRT-related hypomania. CONCLUSION DRT-related hypomania and mania are relevant comorbidities in PD. DRT-related hypomania may exist as a distinct psychiatric symptom complex in young patients with early disease onset. Different patient profiles likely underlie DRT-related hypomania and mania.

Subjective perceived outcome of subthalamic deep brain stimulation in Parkinson's disease one year after surgery

OBJECTIVES Dissatisfaction with subthalamic deep brain stimulation (STN-DBS) despite motor improvements has been observed in Parkinsons disease (PD). Hence, we compared patients subjective perceived outcome 12 months after surgery (12mFU) with clinical measures to identify risk factors of dissatisfaction. METHODS Patients were examined at baseline and 12mFU. Quality of life (QoL), neuropsychiatric, cognitive and neurological functioning was measured. Patients were classified concerning their subjective outcome (negative = dissatisfaction; mixed; positive = satisfaction) at 12mFU using semi-structured interviews. First, the three groups were compared concerning interview statements. Second, repeated measures ANOVAs with group as between-subjects factor were applied to find significant effects of time, group, or interaction. Third, binary logistic regression determined predictors of dissatisfaction. RESULTS Of the 28 enrolled patients, 25% perceived their outcome as negative, 32.1% as mixed, and 42.9% as positive. Concerning interview statements, dissatisfied patients mentioned significantly less often improved QoL and reduced medication, and reported worsening of mental state, and social interaction. For the whole sample, significant improvement over time was found for motor functioning, daily dopamine dosages, and QoL. Apathy significantly worsened over time, but dissatisfied patients were overall more apathetic and depressed than the other groups. Significant interaction of group and time was identified for QoL, which only improved in the mixed and satisfied group. Finally, preoperative apathy and axial symptoms predicted dissatisfaction with STN-DBS. CONCLUSIONS Although motor symptoms and QoL improved in the whole sample, 25% of patients showed disappointment with STN-DBS. Especially apathy predicts dissatisfaction and should be considered preoperatively.

Behavioural and neuroimaging correlates of impaired self-awareness of hypo- and hyperkinesia in Parkinson's disease

INTRODUCTION Anosognosia or impaired self-awareness of motor symptoms (ISAm) has been rarely investigated in Parkinsons disease (PD). We here studied the relationship between ISAm during periods with and without dopaminergic medication (ON- and OFF-state), and clinical, neuropsychological, and neuroimaging data to further elucidate behavioural aspects and the neurobiological underpinnings of ISAm. METHODS Thirty-one right-handed, non-demented, non-depressed PD patients were included. ISAm was evaluated using a recently developed scale that assesses awareness of dyskinesia, resting tremor, and bradykinesia. The test was applied during both ON- and OFF-states. Multiple correlation analyses between ISAm and behavioural data were conducted. In addition, imaging of glucose metabolism using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was performed to investigate the neural basis of ISAm. A multiple regression approach was applied to investigate metabolism alterations related to ISAm. RESULTS In the OFF-state, higher ISAm was associated with left-sided disease onset, older age, and shorter disease duration. Concerning FDG-PET data, there was a significant negative correlation between higher OFF-state ISAm and decreased glucose metabolism in the right inferior frontal gyrus (IFG). In the ON-state, ISAm was not significantly correlated with clinical or behavioural data. However, there was a significant correlation between higher ISAm and an increased metabolism in the bilateral medial frontal gyrus, left IFG, right superior frontal gyrus and right precentral gyrus. CONCLUSION The results support the role of the right hemisphere in awareness of motor symptoms in the OFF-state. In the ON-state, dopaminergic medication and dyskinesia influence ISAm and relate to metabolism changes in bilateral frontal regions.

Impulsivity is Associated with Increased Metabolism in the Fronto-Insular Network in Parkinson’s Disease

Various neuroimaging studies demonstrated that the fronto-insular network is implicated in impulsive behavior. We compared glucose metabolism (as a proxy measure of neural activity) among 24 patients with Parkinson’s disease (PD) who presented with low or high levels of impulsivity based on the Barratt Impulsiveness Scale 11 (BIS) scores. Subjects underwent 18-fluorodeoxyglucose positron emission tomography (FDG-PET) and the voxel-wise group difference of FDG-metabolism was analyzed in Statistical Parametric Mapping (SPM8). Subsequently, we performed a partial correlation analysis between the FDG-metabolism and BIS scores, controlling for covariates (i.e., age, sex, severity of disease and levodopa equivalent daily doses). Voxel-wise group comparison revealed higher FDG-metabolism in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and right insula in patients with higher impulsivity scores. Moreover, there was a positive correlation between the FDG-metabolism and BIS scores. Our findings provide evidence that high impulsivity is associated with increased FDG-metabolism within the fronto-insular network in PD.

Behavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial

BACKGROUND Although subthalamic stimulation is a recognised treatment for motor complications in Parkinsons disease, reports on behavioural outcomes are controversial, which represents a major challenge when counselling candidates for subthalamic stimulation. We aimed to assess changes in behaviour in patients with Parkinsons disease receiving combined treatment with subthalamic stimulation and medical therapy over a 2-year follow-up period as compared with the behavioural evolution under medical therapy alone. METHODS We did a parallel, open-label study (EARLYSTIM) at 17 surgical centres in France (n=8) and Germany (n=9). We recruited patients with Parkinsons disease who were disabled by early motor complications. Participants were randomly allocated (1:1) to either medical therapy alone or bilateral subthalamic stimulation plus medical therapy. The primary outcome was mean change in quality of life from baseline to 2 years. A secondary analysis was also done to assess behavioural outcomes. We used the Ardouin Scale of Behavior in Parkinsons Disease to assess changes in behaviour between baseline and 2-year follow-up. Apathy was also measured using the Starkstein Apathy Scale, and depression was assessed with the Beck Depression Inventory. The secondary analysis was done in all patients recruited. We used a generalised estimating equations (GEE) regression model for individual items and mixed model regression for subscores of the Ardouin scale and the apathy and depression scales. This trial is registered with ClinicalTrials.gov, number NCT00354133. The primary analysis has been reported elsewhere; this report presents the secondary analysis only. FINDINGS Between July, 2006, and November, 2009, 251 participants were recruited, of whom 127 were allocated medical therapy alone and 124 were assigned bilateral subthalamic stimulation plus medical therapy. At 2-year follow-up, the levodopa-equivalent dose was reduced by 39% (-363·3 mg/day [SE 41·8]) in individuals allocated bilateral subthalamic stimulation plus medical therapy and was increased by 21% (245·8 mg/day [40·4]) in those assigned medical therapy alone (p<0·0001). Neuropsychiatric fluctuations decreased with bilateral subthalamic stimulation plus medical therapy during 2-year follow-up (mean change -0·65 points [SE 0·15]) and did not change with medical therapy alone (-0·02 points [0·15]); the between-group difference in change from baseline was significant (p=0·0028). At 2 years, the Ardouin scale subscore for hyperdopaminergic behavioural disorders had decreased with bilateral subthalamic stimulation plus medical therapy (mean change -1·26 points [SE 0·35]) and had increased with medical therapy alone (1·12 points [0·35]); the between-group difference was significant (p<0·0001). Mean change from baseline at 2 years in the Ardouin scale subscore for hypodopaminergic behavioural disorders, the Starkstein Apathy Scale score, and the Beck Depression Inventory score did not differ between treatment groups. Antidepressants were stopped in 12 patients assigned bilateral subthalamic stimulation plus medical therapy versus four patients allocated medical therapy alone. Neuroleptics were started in nine patients assigned medical therapy alone versus one patient allocated bilateral subthalamic stimulation plus medical therapy. During the 2-year follow-up, two individuals assigned bilateral subthalamic stimulation plus medical therapy and one patient allocated medical therapy alone died by suicide. INTERPRETATION In a large cohort with Parkinsons disease and early motor complications, better overall behavioural outcomes were noted with bilateral subthalamic stimulation plus medical therapy compared with medical therapy alone. The presence of hyperdopaminergic behaviours and neuropsychiatric fluctuations can be judged additional arguments in favour of subthalamic stimulation if surgery is considered for disabling motor complications. FUNDING German Federal Ministry of Education and Research, French Programme Hospitalier de Recherche Clinique National, and Medtronic.

Time reproduction deficits in essential tremor patients

Although motor symptoms predominate in essential tremor, increasing evidence indicates additional cognitive deficits. According to the pivotal role of cognitive functioning for temporal information processing and acknowledging the relevance of temporal information processing for movement coordination, we investigated whether essential tremor patients exhibit time reproduction deficits.

Development and psychometric evaluation of a scale to measure impaired self-awareness of hyper- and hypokinetic movements in Parkinson’s disease

OBJECTIVE Patients with Parkinsons disease (PD) can show impaired self-awareness of motor deficits (ISAm). We developed a new scale that measures ISAm severity of hyper- and hypokinetic movements in PD during medication on state and defined its psychometric criteria. METHOD Included were 104 right-handed, non-depressed, non-demented patients. Concerning ISAm, 38 motor symptoms were assessed using seven tasks, which were performed and self-rated concerning presence of deficit (yes/no) by all patients. The whole procedure was videotaped. Motor symptoms were then evaluated by two independent experts, blinded for patients ratings, concerning presence, awareness of deficit, and severity. Exploratory principal component analysis (promax rotation) was applied to reduce items. Principal axis factoring was conducted to extract factors. Reliability was examined regarding internal consistency, split-half reliability, and interrater reliability. Validity was verified by applying two additional measures of ISAm. RESULTS Of the initial 38 symptoms, 15 remained, assessed in five motor tasks and merged to a total severity score. Factor analysis resulted in a four factor solution (dyskinesia, resting tremor right hand, resting tremor left hand, bradykinesia). For all subscales and the total score, measures of reliability (values 0.64-0.89) and validity (effect sizes>0.3) were satisfactory. Descriptive results showed that 66% of patients had signs of ISAm (median 2, range 0-15), with ISAm being most distinct for dyskinesia. CONCLUSIONS We provide the first validation of a test for ISAm in PD. Using this instrument, future studies can further analyze the pathophysiology of ISAm, the psychosocial sequelae, therapeutic strategies and compliance with therapy.