Matthias Löhle

Adherence to Antiparkinson medication in a Multicenter European study

Two small studies reported suboptimal therapy adherence in Parkinsons disease. We conducted a larger multicenter European study to assess medicine‐taking behavior. Parkinsons disease patients taking dopaminergic therapy were enrolled in 8 centers in 5 countries, and disease severity and demographics recorded. Antiparkinson drug adherence was measured for 4 weeks using electronic monitoring bottles which record the date and time of cap opening (Aardex®, Switzerland). One hundred twelve patients, mean age 65 years (standard deviation (SD) 10), with Parkinsons disease for 7.7 (SD 8.2) years completed the study. Total median adherence (doses taken/doses prescribed) was 97.7% (interquartile range [IQ] 90.6–100), days adherence (correct dose days) was 86.2% (IQ 61.1–96.2) and timing adherence (doses taken at correct time intervals) was 24.4% (IQ 5.3–56.5). Fourteen patients (12.5%) took less than 80% of prescribed doses, which was defined as suboptimal adherence. Patients with satisfactory adherence took a median of 8 mg/day (IQ 0–33) less than their prescribed dose of levodopa (P = NS), while suboptimal adherence patients took a median of 481 mg/day (IQ 205–670) less than their prescribed dose (P = 0.0006). The Parkinson motor score was significantly higher in patients with suboptimal adherence at 29 (IQ 20–40), versus those with satisfactory adherence at 19 (IQ 13–26), P = 0.005. Once daily drugs had significantly better adherence when compared with drugs prescribed more frequently (P < 0.0001). Suboptimal therapy adherence is associated with significant deviation from prescribed levodopa doses, despite greater Parkinsons motor severity. Optimizing oral medication intake has a potential role in maximizing the therapy response in Parkinsons disease.

Clinical neuroprotection in Parkinson's disease — Still waiting for the breakthrough

Recent research in the pharmacotherapy of Parkinsons disease (PD) has been able to provide numerous agents for the symptomatic control of motor impairments, but has failed to identify substances capable to slow down or even halt the progression of the disease. In the absence of disease-modifying therapies, affected patients develop marked disability within some years after the onset of motor symptoms, which can be alleviated but eventually not prevented with currently available medical and surgical therapies. Despite promising results from preclinical studies, outcomes of clinical neuroprotection trials have been repeatedly disappointing, which calls for a review of our approach to this topic. This article attempts to explain the need for neuroprotective therapies in PD, discusses results and limitations of previous clinical trials and provides some food for thought for the future research of neuroprotection in PD. Previous experiences from neuroprotection studies may have been discouraging, but also teach us some important lessons for the next generation of preclinical and clinical trials. Firstly, our currently used animal models for PD need to be refined in order to more reliably predict the efficacy of putative neuroprotective agents in subsequent clinical studies. Furthermore, changes in the methodology and design of future neuroprotection trials are required in order to exclude an impact of confounding symptomatic effects on observations. Finally, coordination and concentration of future research on the most promising agents will be necessary in order to accelerate the search for neuroprotective therapies in PD. Just as the pathogenesis of the disease is manifold, it may be this multilateral approach that eventually leads us to a breakthrough in finding neuroprotective agents for PD, if they exist.

Beyond tremor and rigidity: non-motor features of Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease and primarily considered as a movement disorder defined by the presence of motor symptoms, such as bradykinesia, tremor and rigidity. However, it is nowadays widely accepted that PD is associated with a wide variety of non-motor features, which affect the vast majority of patients during the course of the disease and may even precede the onset of motor symptoms. The spectrum of these non-motor disturbances is very broad and comprises neuropsychiatric conditions, such as depression, dementia and hallucinations, as well as autonomic, sensory and sleep disorders. Physicians need to be aware of these non-motor features, since they have substantial impact on the health-related quality of life of PD patients, even ahead of motor symptoms. This article aims to provide an overview of frequently observed non-motor features in PD and discusses prospects and limitations of currently available options for symptomatic treatment of these disturbances.

Fetal body weight and the development of the control of the cardiovascular system in fetal sheep

Reduced birth weight predisposes to cardiovascular diseases in later life. We examined in fetal sheep at 0.76 (n= 18) and 0.87 (n= 17) gestation whether spontaneously occurring variations in fetal weight affect maturation of autonomic control of cardiovascular function. Fetal weights at both gestational ages were grouped statistically in low (LW) and normal weights (NW) (P < 0.01). LW fetuses were within the normal weight span showing minor growth dysproportionality at 0.76 gestation favouring heart and brain, with a primary growth of carcass between 0.76 and 0.87 gestation (P < 0.05). While twins largely contributed to LW fetuses, weight differences between singletons and twins were absent at 0.76 and modest at 0.87 gestation, underscoring the fact that twins belong to normality in fetal sheep not constituting a major malnutritive condition. Mean fetal blood pressure (FBP) of all fetuses was negatively correlated to fetal weight at 0.76 but not 0.87 gestation (P < 0.05). At this age, FBP and baroreceptor reflex sensitivity were increased in LW fetuses (P < 0.05), suggesting increased sympathetic activity and immaturity of circulatory control. Development of vagal modulation of fetal heart rate depended on fetal weight (P < 0.01). These functional associations were largely independent of twin pregnancies. We conclude, low fetal weight within the normal weight span is accompanied by a different trajectory of development of sympathetic blood pressure and vagal heart rate control. This may contribute to the development of elevated blood pressure in later life. Examination of the underlying mechanisms and consequences may contribute to the understanding of programming of cardiovascular diseases.

Differentiation Efficiency of Induced Pluripotent Stem Cells Depends on the Number of Reprogramming Factors

Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by retroviral overexpression of the transcription factors Oct4, Sox2, Klf4, and c‐Myc holds great promise for the development of personalized cell replacement therapies. In an attempt to minimize the risk for chromosomal disruption and to simplify reprogramming, several studies demonstrated that a reduced set of reprogramming factors is sufficient to generate iPSC, albeit at lower efficiency. To elucidate the influence of factor reduction on subsequent differentiation, we compared the efficiency of neuronal differentiation in iPSC generated from postnatal murine neural stem cells with either one (Oct4; iPSC1F‐NSC), two (Oct4, Klf4; iPSC2F‐NSC), or all four factors (iPSC4F‐NSC) with those of embryonic stem cells (ESCs) and iPSC produced from fibroblasts with all four factors (iPSC4F‐MEF). After 2 weeks of coculture with PA6 stromal cells, neuronal differentiation of iPSC1F‐NSC and iPSC2F‐NSC was less efficient compared with iPSC4F‐NSC and ESC, yielding lower proportions of colonies that stained positive for early and late neuronal markers. Electrophysiological analyses after 4 weeks of differentiation identified functional maturity in neurons differentiated from ESC, iPSC2F‐NSC, iPSC4F‐NSC, and iPSC4F‐MEF but not in those from iPSC1F‐NSC. Similar results were obtained after hematoendothelial differentiation on OP9 bone marrow stromal cells, where factor‐reduced iPSC generated lower proportions of colonies with hematoendothelial progenitors than colonies of ESC, iPSC4F‐NSC, and iPSC4F‐MEF. We conclude that a reduction of reprogramming factors does not only reduce reprogramming efficiency but may also worsen subsequent differentiation and hinder future application of iPSC in cell replacement therapies. STEM CELLS 2012;30:570–579

Non-motor features of Parkinson's disease: depression and dementia

Parkinsons disease (PD) is the second most common neurodegenerative disease and primarily considered as a movement disorder defined by the presence of motor symptoms, such as bradykinesia, tremor and rigidity. However, it is nowadays widely recognized that in addition there is impairment of cognitive function, mood and the autonomic nervous system in a high percentage of PD patients, which is sometimes even more harming quality of life. These symptoms not only occur during the course of the disease but may even precede the onset of motor symptoms. Typical examples of non-motor features of PD are depression, constipation, REM sleep behaviour disorder, and hyposmia.

Developmental changes in cerebral autoregulatory capacity in the fetal sheep parietal cortex.

We validated laser Doppler flowmetry (LDF) for long‐term monitoring and detection of acute changes of local cerebral blood flow (lCBF) in chronically instrumented fetal sheep. Using LDF, we estimated developmental changes of cerebral autoregulation. Single fibre laser probes (0.4 mm in diameter) were implanted in and surface probes were placed on the parietal cerebral cortex at 105 ± 2 (n= 7) and 120 ± 2 days gestational age (dGA, n= 7). Basal lCBF was monitored over 5 days followed by a hypercapnic challenge (fetal arterial partial pressure of CO2, Pa,CO2: 83 ± 3 mmHg) during which lCBF changes obtained by LDF were compared to those obtained with coloured microspheres (CMSs). Mean arterial blood pressure (MABP) was increased and decreased using phenylephrine and sodium nitroprusside at 110 ± 2 and 128 ± 2 dGA. Intracortical and cortical surface laser probes gave stable measurements over 5 days. The lCBF increase during hypercapnia obtained by LDF correlated well with flows obtained using CMS (r = 0.89, P < 0.01). The signals of intracortical and surface laser probes also correlated well (r = 0.91, P < 0.01). Gliosis of 0.35 ± 0.06 mm around the tip of intracortical probes did not affect the measurements. The range of MABP over which cerebral autoregulation was observed increased from 20–48 mmHg at 110 dGA to 35 to > 95 mmHg at 128 dGA (P < 0.05). Since MABP increased from 33 to 54 mmHg over this period (P < 0.01), the range between the lower limit of cerebral autoregulation and the MABP increased from 13 mmHg at 110 dGA to 19 mmHg at 128 dGA (P < 0.01). LDF is a reliable tool to assess dynamic changes in cerebral perfusion continuously in fetal sheep.

Chocolate consumption is increased in Parkinson's disease. Results from a self-questionnaire study.

Clinical observations in Parkinson’s disease (PD) patients suggested an increased chocolate consumption. Chocolate contains high contents of various biogenic amines potentially influencing brain monoamine metabolism. 498 PD patients and their partners were evaluated by a structured self-questionnaire asking for consumption of chocolate and non-chocolate sweets, changes in chocolate consumption during the disease course, and depressive symptoms. Questionnaires from 274 patients (55 %) and 234 controls were eligible for further analysis. Consumption of chocolate was significantly higher in PD patients compared to controls, while consumption of non-chocolate sweets was similar in both groups. Our study suggests that chocolate consumption is increased in PD independent of concomitant depressive symptoms measured by BDI-1. Although reasons for increased chocolate consumption in PD remain elusive, it may hypothetically be a consequence of the high content of various biogenic amines and/or caffeine analogues with potential antiparkinsonian effects.

Controversies in neurology: why monoamine oxidase B inhibitors could be a good choice for the initial treatment of Parkinson's disease.

BackgroundEarly initiation of pharmacotherapy in Parkinsons disease (PD) is nowadays widely advocated by experts since the delay of treatment has shown to be associated with a significant deterioration of health related quality of life in affected patients. Due to marked advances in PD treatment during the last decades, physicians are nowadays fortunately equipped with a variety of substances that can effectively ameliorate emerging motor symptoms of the disease, among them levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors. Despite numerous drug intervention trials in early PD, there is however still ongoing controversy among neurologists which substance to use for the initial treatment of the disease.DiscussionIn multiple studies, MAO-B inhibitors, such as selegiline and rasagiline, have shown to provide mild symptomatic effects, delay the need for levodopa, and to reduce the incidence of motor fluctuations. Although their symptomatic efficacy is inferior compared to dopamine agonists and levodopa, MAO-B inhibitors undoubtedly have fewer side effects and are easy to administer. In contrary to their competitors, MAO-B inhibitors may furthermore offer a chance for disease modification, which so far remains a major unmet need in the management of PD and eventually makes them ideal candidates for the early treatment of the disease.SummaryMAO-B inhibitors may constitute a preferable therapeutic option for early PD, mainly due to their favourable safety profile and their putative neuroprotective capabilities. Since the symptomatic effects of MAO-B inhibitors are comparatively mild, dopamine agonists and levodopa should however be considered for initial treatment in those PD patients, in whom robust and immediate symptomatic relief needs to be prioritized.

Potassium channel blocker 4‐aminopyridine is effective in interictal cerebellar symptoms in episodic ataxia type 2 — A video case report

Episodic ataxia type 2 (EA2) is an autosomal‐dominant hereditary disorder clinically characterized by recurrent attacks of vertigo, imbalance and ataxia. Studies have shown that 4‐aminopyridine (4‐AP) is capable to prevent these attacks. However, there are no reports whether 4‐AP is able to attenuate interictal cerebellar ataxia. Using the scale for assessment and rating of ataxia (SARA), we examined the efficacy of 4‐AP on interictal ataxia in a 63‐year‐old female patient who suffered from EA2 since the age of 57. EA2 was diagnosed based on clinical criteria and not genetically proven. When treatment with 4‐AP was paused the patient was suffering from marked gait and stance ataxia. After re‐initiation of treatment with 5 mg 4‐AP t.i.d., there was pronounced improvement in gait and stance ataxia. Within 24 hours SARA score lowered from 8.5 to 4.5 points. We conclude that 4‐AP may be beneficial for interictal cerebellar ataxia in late onset EA2.