Mareike Fauser

Immediate effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms in Parkinson's disease

OBJECTIVE To assess the immediate effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) on nonmotor symptoms (NMS) in Parkinsons disease (PD). BACKGROUND Immediate effects of STN-DBS on motor functions are well accepted, but similar data on NMS are mainly lacking. METHODS 34 PD patients who received bilateral STN-DBS were examined in medication Off state for frequency and severity of 10 NMS (dysphagia, anxiety, depression, fatigue, excessive sweating, inner restlessness, pain, concentration/attention, dizziness, bladder urgency) using a visual analogue scale (VAS) with STN-DBS Off and On. Motor assessments were done using UPDRS part III. RESULTS Independent of STN-DBS status, most frequent NMS was fatigue (85% of patients), followed by problems with concentration/attention (71%) and inner restlessness (53%). Frequencies of most NMS were similar in both STN-DBS statuses, while only inner restlessness was significantly decreased by STN-DBS. Severities of most NMS were significantly improved by STN-DBS on the cohort level, while only excessive sweating, pain and dizziness did not show significant severity changes. However, variable proportions of patients (15-71%, depending on the NMS) reported relevant improvements (>10% on VAS) by STN-DBS with fatigue showing the largest proportion of patients with symptom improvement (71%). There were no correlations of severity changes of NMS with motor improvement, demographic data and medication. CONCLUSION STN-DBS does not have major immediate effects on frequencies of NMS, but improves most NMS particularly psychiatric symptoms such as depression, anxiety and fatigue in a variable subset of patients. There is no indication that STN-DBS worsens NMS.

Rostro-caudal gradual loss of cellular diversity within the periventricular regions of the ventricular system.

Neurogenesis occurs constitutively within the periventricular region (PVR) of the lateral ventricles (LV) of the adult mammalian brain. The occurrence of adult neurogenesis within the PVR outside the neurogenic niche of the LV remains controversial, but neural stem cells can be isolated from PVR of the whole ventricular system. The histological basis of this phenomenon including the regional differences of cellular phenotypes within the PVRs is still enigmatic. The occurrence of neurogenesis or manipulable progenitor cells in caudal parts of the adult brain is however one prerequisite for orthotopic regenerative approaches in Parkinsons disease (PD) and other disorders of the midbrain/brainstem. Using quantitative immunohistochemical techniques and electron microscopy, we found a rostro‐caudal gradual loss of cellular diversity within the PVR throughout the whole ventricular axis with loss of transit amplifying epidermal growth factor‐receptor+ type C cells in all parts caudal to the LV, a gradual reduction from rostral to caudal of both stem cells (type B cells or astrocytes) without signs of proliferation outside the PVR of the LV as well as neuroblasts‐like cells (polysialylated neural cell adhesion molecule [PSA‐NCAM]+, but doublecortin negative cells) with a different morphology compared with neuroblasts of the PVR of the LV. Electron microscopy confirmed these immunohistochemical data. The proportion of Nestin+/CD24+ cells and Nestin+/S100β+ ependymal cells were consecutively increased in the PVR from rostral to caudal, and ultrastructural analysis showed a region‐specific morphology with darker cytoplasm with occasional large lipid droplets as well as indented nuclei within the caudal PVRs. The strong correlation of neuroblast‐like cells with the number of neurosphere‐forming cells suggests that a quiescent subtype of PSA‐NCAM+ cells might be a source of neurosphere‐forming cells. We did not find any evidence for neurogenesis or the occurrence of neuroprogenitors within the substantia nigra or other parts of the midbrain/brainstem outside the PVR. Our data provide the histological framework for future studies on orthotopic regenerative approaches in PD by recruiting endogenous predopaminergic progenitors from the midbrain PVR. STEM CELLS 2009;27:928–941

Origin-Dependent Neural Cell Identities in Differentiated Human iPSCs In Vitro and after Transplantation into the Mouse Brain

The differentiation capability of induced pluripotent stem cells (iPSCs) toward certain cell types for disease modeling and drug screening assays might be influenced by their somatic cell of origin. Here, we have compared the neural induction of human iPSCs generated from fetal neural stem cells (fNSCs), dermal fibroblasts, or cord blood CD34(+) hematopoietic progenitor cells. Neural progenitor cells (NPCs) and neurons could be generated at similar efficiencies from all iPSCs. Transcriptomics analysis of the whole genome and of neural genes revealed a separation of neuroectoderm-derived iPSC-NPCs from mesoderm-derived iPSC-NPCs. Furthermore, we found genes that were similarly expressed in fNSCs and neuroectoderm, but not in mesoderm-derived iPSC-NPCs. Notably, these neural signatures were retained after transplantation into the cortex of mice and paralleled with increased survival of neuroectoderm-derived cells in vivo. These results indicate distinct origin-dependent neural cell identities in differentiated human iPSCs both in vitro and in vivo.

Intrastriatal Transplantation of Adult Human Neural Crest-Derived Stem Cells Improves Functional Outcome in Parkinsonian Rats

Parkinsons disease (PD) is considered the second most frequent and one of the most severe neurodegenerative diseases, with dysfunctions of the motor system and with nonmotor symptoms such as depression and dementia. Compensation for the progressive loss of dopaminergic (DA) neurons during PD using current pharmacological treatment strategies is limited and remains challenging. Pluripotent stem cell‐based regenerative medicine may offer a promising therapeutic alternative, although the medical application of human embryonic tissue and pluripotent stem cells is still a matter of ethical and practical debate. Addressing these challenges, the present study investigated the potential of adult human neural crest‐derived stem cells derived from the inferior turbinate (ITSCs) transplanted into a parkinsonian rat model. Emphasizing their capability to give rise to nervous tissue, ITSCs isolated from the adult human nose efficiently differentiated into functional mature neurons in vitro. Additional successful dopaminergic differentiation of ITSCs was subsequently followed by their transplantation into a unilaterally lesioned 6‐hydroxydopamine rat PD model. Transplantation of predifferentiated or undifferentiated ITSCs led to robust restoration of rotational behavior, accompanied by significant recovery of DA neurons within the substantia nigra. ITSCs were further shown to migrate extensively in loose streams primarily toward the posterior direction as far as to the midbrain region, at which point they were able to differentiate into DA neurons within the locus ceruleus. We demonstrate, for the first time, that adult human ITSCs are capable of functionally recovering a PD rat model.

Effects of rasagiline on olfactory function in patients with Parkinson's disease

Impairment of olfactory function is a well‐recognized nonmotor manifestation of Parkinsons disease (PD). The aim of this investigation was to determine if the MAO‐B inhibitor rasagiline can improve olfaction in PD patients.

Assessment of Nonmotor Fluctuations Using a Diary in Advanced Parkinson's Disease

BACKGROUND Since previous studies aimed to study nonmotor symptom (NMS) fluctuations in direct conjunction with motor oscillations, there are no data available on the temporal context of NMS fluctuations and motor oscillations in advanced Parkinsons disease (PD). OBJECTIVE To evaluate circadian patterns and temporal connections of NMS and motor fluctuations in PD. METHODS 15 controls, 17 non-fluctuating and 15 fluctuating PD patients completed two diaries by rating 4 key psychiatric (anxiety, depressive mood, inner restlessness, concentration/attention deficits), fatigue and 4 autonomic NMS (excessive sweating, sialorrhea, bladder urgency, dizziness) absent or present and motor function (Off, On with/without dyskinesia, and asleep) for every hour for 5 consecutive days. RESULTS NMS Off state hours (hours with NMS rated as present) were less frequent compared to motor Off state hours and NMS On-Off-switches were less prevalent compared to those of the motor state. Off time and number of On-Off-switches of psychiatric NMS were moderately correlated with motor Off time and number of motor On-Off switches on the individual patient level. Changes in NMS state occurred largely independent of changes in motor states with concordance rates of only 26-43% of all NMS changes for psychiatric and 7-17% for autonomic NMS. In controls and non-fluctuating PD patients, there were no NMS state switches in concordance to motor state switches. CONCLUSION We provide first data on the temporal context of NMS fluctuations showing similar frequencies of psychiatric NMS Off, fatigue Off and motor Off times as well as their On-Off-fluctuations, but low concordance rates of NMS with motor On-Off-state switches. We found no evidence for NMS fluctuations in non-fluctuating PD patients. Our data implicate similar fluctuation patterns of mood NMS and motor function without close timing and/or different kinetics.

Intraindividual Variability of Nonmotor Fluctuations in Advanced Parkinson’s Disease

Nonmotor symptoms (NMS) fluctuate in conjunction with motor oscillations in advanced Parkinsons disease (PD), though little is known about the variability of NMS fluctuations in individual patients. We aimed to assess within-patient variability in frequency and severity of NMS during a series of five patient-perceived motor On and Off periods in 38 fluctuating PD patients from the multicenter NonMotorFluctuations in PD study using a visual analogue scale. NMS frequency and severity appeared moderately variable in both motor states within individual patients. Symptom severity ranges between motor states showed high variability and were larger in motor Off states for most NMS.

Timing and Kinetics of Nonmotor Fluctuations in Advanced Parkinson’s Disease

BACKGROUND Nonmotor symptoms (NMS) are known to fluctuate together with motor oscillations in advanced PD, but their timing and kinetics remains enigmatic. OBJECTIVE To evaluate timing and kinetics of NMS fluctuations. METHODS Analysis of diary data from 17 fluctuating PD patients. Diaries were completed by rating NMS as absent (defined herein as NMS On state) or present (NMS Off state) and motor function for every hour for 5 consecutive days. Timing and kinetics were analyzed by synchronizing motor Off periods and subsequent cross-classification of NMS Off periods for each motor Off hour into 2×2 contingency tables. RESULTS We found clear temporal connections of NMS Off periods with motor Off periods only for anxiety/depression, concentration/attention deficiency and bladder urgency. Psychiatric NMS Off periods had a longer duration (median: 3-4 hours) compared to motor Off periods (2 hours; P < 0.05, Mann-Whitney U-test). CONCLUSIONS Our data on timing and kinetics of NMS fluctuations show close temporal connection with motor Off periods only for mood and cognitive symptoms. Variances in both timing and/or kinetics of NMS fluctuations might explain both the weak/absent correlations of NMS and motor symptom severity in fluctuating patients and the rather low rates of simultaneous switches between On and Off states for NMS and motor function.

Correlation of Quantitative Motor State Assessment Using a Kinetograph and Patient Diaries in Advanced PD: Data from an Observational Study

Introduction Effective management and development of new treatment strategies for response fluctuations in advanced Parkinson’s disease (PD) largely depends on clinical rating instruments such as the PD home diary. The Parkinson’s kinetigraph (PKG) measures movement accelerations and analyzes the spectral power of the low frequencies of the accelerometer data. New algorithms convert each hour of continuous PKG data into one of the three motor categories used in the PD home diary, namely motor Off state and On state with and without dyskinesia. Objective To compare quantitative motor state assessment in fluctuating PD patients using the PKG with motor state ratings from PD home diaries. Methods Observational cohort study on 24 in-patients with documented motor fluctuations who completed diaries by rating motor Off, On without dyskinesia, On with dyskinesia, and asleep for every hour for 5 consecutive days. Simultaneously collected PKG data (recorded between 6 am and 10 pm) were analyzed and calibrated to the patient’s individual thresholds for Off and dyskinetic state by novel algorithms classifying the continuous accelerometer data into these motor states for every hour between 6 am and 10 pm. Results From a total of 2,040 hours, 1,752 hours (87.4%) were available for analyses from calibrated PKG data (7.5% sleeping time and 5.1% unclassified motor state time were excluded from analyses). Distributions of total motor state hours per day measured by PKG showed moderate-to-strong correlation to those assessed by diaries for the different motor states (Pearson’s correlations coefficients: 0.404–0.658), but inter-rating method agreements on the single-hour-level were only low-to-moderate (Cohen’s κ: 0.215–0.324). Conclusion The PKG has been shown to capture motor fluctuations in patients with advanced PD. The limited correlation of hour-to-hour diary and PKG recordings should be addressed in further studies.

Impulsiv-zwanghafte Verhaltensstörungen in einer deutschen Stichprobe ambulant versorgter Parkinson-Patienten

BACKGROUND Impulsive-compulsive behaviours (ICBs) are frequent complications of Parkinsons disease (PD), associated with treatment by dopamine agonists (DAs). These include impulse control disorders (ICDs), repetitive behaviour (RB) and the dopamine-dysregulation syndrome (DDS). METHODS A subsample of 72 patients of a large longitudinal study (n = 739) was screened with the Questionnaire for Impulsive-Compulsive Disorders in Parkinsons disease (QUIP). Results were associated with socio-demographic, clinical and neuropsychological parameters. RESULTS A large proportion of the sample reported ICBs (60%), RBs were most frequent (47 %). Patients with ICBs consumed higher doses of DAs (343 ± 177 mg vs. 390 ± 153 mg; p < 0.01). Pramipexole was associated with RB but not ICDs (273 ± 225 mg and 53 ± 106 mg vs. 151 ± 209 mg in patients without ICB). Patients with ICDs reported more dyskinesias (UPDRS IV: 1.78 ± 1.6 vs. 0.55 ± 1.1 points; p = 0.012) and patients with multiple ICBs a longer duration of PD (9.3 ± 5.0 vs. 6.2 ± 4.0 years; p = 0.026) and worse quality of life (PDQ39: 29.9 ± 13.8 vs. 20.3 ± 13.4 points; p = 0.036) compared to patients without any ICB. CONCLUSIONS ICBs are frequent even in outpatients with moderate duration and severity of PD and associated with DA dose. Because of possible serious psychosocial consequences, detecting and managing them is of high importance.