Motor symptoms in Parkinson’s disease (PD) are tightly linked to the degeneration of substantia nigra dopaminergic neurons and their projections into the striatum. Moreover, a broad range of non-motor symptoms like anxiety and depression frequently occur in PD, most likely related to the loss of serotonergic neurons and their projections into corresponding targets. Strikingly, nigral dopaminergic neurons and raphe serotonergic neurons are severely affected in PD showing characteristic hallmarks of PD neuropathology, in particular alpha-synuclein containing Lewy bodies and Lewy neurites. So far, the initial events underlying neurodegenerative processes in PD are not well understood. Several observations, however, indicate that neurites and synapses of diseased neurons may be the first subcellular compartments compromised by alpha-synuclein associated pathology. In particular axonal pathology and deficits in axonal transport may be leading to the onset of synucleinopathies such as PD. This review will highlight current findings derived from imaging and neuropathological studies in PD patients, as well as cellular and animal PD models, which define the initial underlying structural and molecular events within dopaminergic and serotonergic circuits leading to the ‘dying back’ degeneration of axonal projections in PD.

Inhibitors of monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) are major strategies to reduce levodopa degradation and thus to increase and prolong its effect in striatal dopaminergic neurotransmission in Parkinson’s disease patients. While selegiline/rasagiline and tolcapone/entacapone have been available on the market for more than one decade, safinamide and opicapone have been approved in 2015 and 2016, respectively. Meanwhile, comprehensive data from several post-authorization studies have described the use and specific characteristics of the individual substances in clinical practice under real-life conditions. Here, we summarize current knowledge on both medication classes, with a focus on the added clinical value in Parkinson’s disease. Furthermore, we outline practical considerations in the treatment of motor fluctuations and provide an outlook on ongoing studies with MAO-B and COMT inhibitors.

Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines. In the majority, somatic copy number variants (CNVs) were identified. A subset with available matched donor DNA was selected for comparative exome sequencing. We identified single nucleotide variants (SNVs) at different allelic frequencies in each clone with high variability in mutational load. Low frequencies of variants in parental fibroblasts highlight the importance of germline samples. Somatic variant number was independent from reprogramming, cell type and passage. Comparison with disease genes and prediction scores suggest biological relevance for some variants. We show that high-throughput sequencing has value beyond SNV detection and the requirement to individually evaluate each clone.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers’ burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients’ CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients’ functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers’ burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers’ burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients’ functional status (r_p = −0.555, p < 0.001, n = 242). It was influenced by the CGs’ own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients’ wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs’ depression (r_p = 0.627, p < 0.001, n = 234), anxiety (r_p = 0.550, p < 0.001, n = 234), and poorer physical condition (r_p = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients’ impairment in daily routine (r_s = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs’ lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs’ work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.

Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder linked to expanded CAG-triplet nucleotide repeats within the huntingtin gene. Intracellular huntingtin aggregates are present in neurons of distinct brain areas, among them regions of adult neurogenesis including the hippocampus and the subventricular zone/olfactory bulb system. Previously, reduced hippocampal neurogenesis has been detected in transgenic rodent models of HD. Therefore, we hypothesized that mutant huntingtin also affects newly generated neurons derived from the subventricular zone of adult R6/2 HD mice. Results: We observed a redirection of immature neuroblasts towards the striatum, however failed to detect new mature neurons. We further analyzed adult neurogenesis in the granular cell layer and the glomerular layer of the olfactory bulb, the physiological target region of subventricular zone-derived neuroblasts. Using bromodeoxyuridine to label proliferating cells, we observed in both neurogenic regions of the olfactory bulb a reduction in newly generated neurons. Conclusion: These findings suggest that the striatal environment, severely affected in R6/2 mice, is capable of attracting neuroblasts, however this region fails to provide sufficient signals for neuronal maturation. Moreover, in transgenic R6/2 animals, the hostile huntingtin-associated microenvironment in the olfactory bulb interferes with the survival and integration of new mature neurons. Taken together, endogenous cell repair strategies in HD may require additional factors for the differentiation and survival of newly generated neurons both in neurogenic and non-neurogenic regions.

Parkinson's disease, neuropathologically defined by the aggregation of α‐synuclein, is characterized by neuropsychiatric symptoms such as depression and anxiety preceding the onset of motor symptoms. A loss of serotonergic neurons or their projections into the hippocampus and alterations in serotonin release may be linked to these symptoms. Here, we investigate the effect of human A53T α‐synuclein on serotonergic neurons using 12‐months‐old transgenic mice. We detected human α‐synuclein in the perikarya of brainstem median and dorsal raphe neurons as well as in serotonergic fibers in the hippocampus. Despite intracellular α‐synuclein accumulation there was no loss of serotonergic neurons in dorsal and median raphe nuclei of A53T α‐synuclein mice. However, serotonin levels were significantly reduced in the brainstem. In addition, serotonergic fiber density in the dorsal dentate gyrus was significantly less dense in transgenic mice. Interestingly, we detected a significantly compromised increase in doublecortin+ neuroblasts after chronic treatment with fluoxetine at the site of reduced serotonergic innervation, the infrapyramidal blade of the dorsal dentate gyrus in A53T α‐synuclein mice. This suggests that α‐synuclein affects serotonergic projections in a spatially distinct pattern within the hippocampus thereby influencing the response to antidepressant treatment. image A transgenic mouse model of Parkinson's disease (PD) shows α‐synuclein expression in serotonergic neurons of raphe nuclei. Besides lower serotonin levels in the raphe nuclei, a topographical restricted reduction in serotonergic fiber density was present in the hippocampus accompanied by an impaired fluoxetine‐response of hippocampal neuroblasts. In conclusion, α‐synuclein in the serotonergic system may account for psychiatric symptoms in PD. DR, dorsal raphe nucleus; MnR, median raphe nucleus.