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Parkinson’s disease (PD) is the second most common neurodegenerative disorder, with increasing numbers of affected patients. Many patients lack adequate care due to insufficient specialist neurologists/geriatricians, and older patients experience difficulties traveling far distances to reach their treating physicians. A new option for these obstacles would be telemedicine and wearables. During the last decade, the development of wearable sensors has allowed for the continuous monitoring of bradykinesia and dyskinesia. Meanwhile, other systems can also detect tremors, freezing of gait, and gait problems. The most recently developed systems cover both sides of the body and include smartphone apps where the patients have to register their medication intake and well-being. In turn, the physicians receive advice on changing the patient’s medication and recommendations for additional supportive therapies such as physiotherapy. The use of smartphone apps may also be adapted to detect PD symptoms such as bradykinesia, tremor, voice abnormalities, or changes in facial expression. Such tools can be used for the general population to detect PD early or for known PD patients to detect deterioration. It is noteworthy that most PD patients can use these digital tools. In modern times, wearable sensors and telemedicine open a new window of opportunity for patients with PD that are easy to use and accessible to most of the population.

Non-motor symptoms (NMS) occur in patients with cervical dystonia (CD) but with variable frequencies and impact on health-related quality of life (HRQoL). To define non-motor and motor profiles and their respective impact on HRQoL in CD patients using the newly validated Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest). In an observational prospective multicentre case–control study, we enrolled 61 patients with CD and 61 age- and sex-matched healthy controls (HC) comparing demographic data, motor and non-motor symptoms and HRQoL measurements. 95% CD patients reported at least one NMS. Mean total NMS score was significantly higher in CD patients (5.62 ± 3.33) than in HC (1.74 ± 1.52; p r = 0.72, EQ-5D: r = − 0.59; p

Levodopa/carbidopa intestinal gel (LCIG) infusion is an effective escalating therapy in patients with Parkinson disease (PD) suffering from motor fluctuations and dyskinesia. Levodopa/carbidopa given continuously as infusion provides an optimized application of the most effective and best tolerable antiparkinsonian drug. It has been proven to have a superior motor effect compared with oral levodopa and to improve also non-motor symptoms. However, invasiveness, discomfort resulting from carrying an external device, and side effects associated with the way of administration limit its application in PD patients. At present, there are no guidelines that delineate to which patients LCIG should be offered as monotherapy, in combination with oral and/or transdermal medication, or as additional therapy to deep brain stimulation (DBS). Based on clinical studies, we propose an expert consensus for neurologists addressing the question when LCIG therapy should be recommended and in which cases LCIG infusion is suggested in combination with other antiparkinsonian drugs and/or DBS. We describe how LCIG should be initiated and what we consider necessary for clinical follow-up. We suggest an algorithm facilitating decision-making with respect to the currently available invasive PD therapies, namely infusion with subcutaneous apomorphine, LCIG, and DBS.

This article summarises the noteworthy contribution of Professor Jellinger to the understanding of Parkinson's disease (PD) as a disease affecting multiple body- and neurotransmitter-systems. Phosphorylated alpha-synuclein and the formation of Lewy pathology as neuropathological hallmarks of PD seem to spread from the enteric nervous system and the olfactory bulb in a rostrocranial direction to the CNS. Subsequently, a progressive degeneration of the dopaminergic-nigrostriatal system and widespread extranigral pathology affecting different anatomical structures and neurotransmitters are induced causing the various non-motor and motor symptoms of PD.

Currently, we still lack effective measures to modify disease progression in neurodegenerative diseases. Iron-containing proteins play an essential role in many fundamental biological processes in the central nervous system. In addition, iron is a redox-active ion and can induce oxidative stress in the cell. Although the causes and pathology hallmarks of different neurodegenerative diseases vary, iron dyshomeostasis, oxidative stress and mitochondrial injury constitute a common pathway to cell death in several neurodegenerative diseases. MRI is capable of depicting iron content in the brain, and serves as a potential biomarker for early and differential diagnosis, tracking disease progression and evaluating the effectiveness of neuroprotective therapy. Iron chelators have shown their efficacy against neurodegeneration in a series of animal models, and been applied in several clinical trials. In this review, we summarize recent developments on iron dyshomeostasis in Parkinson's disease, Alzheimer's disease, Friedreich ataxia, and Huntington's disease.

Physicians, caregivers and patients themselves must be alert to the onset of and changes in motor and non-motor features during the course of Parkinson's disease (PD). Parallel laboratory routine assessments are necessary because of the evolving impairment of the general health status of the individual. A number of potential biomarkers for the diagnosis of PD are currently under investigation, with diagnosis early in the disease course a particular goal, even before the onset of motor symptoms. The aim of this guideline article is to provide user-friendly, clinical evidence-based recommendations for using laboratory pathological testing for the diagnosis and differential diagnosis of PD, for assessing its time course, and managing complications of long-term dopaminergic therapy and the disabling motor features that develop in the later stages of the disease.

General medical problems and complications have a major impact on the quality of life in all stages of Parkinson’s disease. To introduce an effective treatment, a comprehensive analysis of the various clinical symptoms must be undertaken. One must distinguish between (1) diseases which arise independently of Parkinson’s disease, and (2) diseases which are a direct or indirect consequence of Parkinson’s disease. Medical comorbidity may induce additional limitations to physical strength and coping strategies, and may thus restrict the efficacy of the physical therapy which is essential for treating hypokinetic-rigid symptoms. In selecting the appropriate medication for the treatment of any additional medical symptoms, which may arise, its limitations, contraindications and interactions with dopaminergic substances have to be taken into consideration. General medical symptoms and organ manifestations may also arise as a direct consequence of the autonomic dysfunction associated with Parkinson’s disease. As the disease progresses, additional non-parkinsonian symptoms can be of concern. Furthermore, the side effects of Parkinson medications may necessitate the involvement of other medical specialists. In this review, we will discuss the various general medical aspects of Parkinson’s disease.

Data on frequency, severity and correlations of NMS with motor complications are only available for a limited number of NMS. The NMS Scale (NMSS) is a validated tool to assess a broad range of NMS, which has not been used in NMS fluctuations. We assessed fluctuations of a broad range of non-motor symptom (NMS) for a 1-month time period in fluctuating Parkinson's disease (PD) in a multicenter cross-sectional study using the NMSS assessing NMS in motor On (NMSSOn) and Off state (NMSSOff) combined with clinical NMS and motor function scoring in 100 fluctuating PD patients. ΔNMSSOn/Off was defined as the differences of NMSS scores between On and Off. Complete NMSS datasets were available from 73 patients (53 % men; age: 68.2 ± 9.7 years) with mean total NMSS score in On state of 41.5 ± 37.6 and in Off state of 75.6 ± 42.3 (P < 0.001). Scores were higher in Off compared to On state for all domains except for domain "perceptual problems/hallucinations" (P = 0.608). Clinimetric properties of the NMSS were similar to those reported previously for NMS assessments independent of motor oscillations. NMSSOn, NMSSOff and ΔNMSSOn/Off showed weak to moderate correlations with demographics, indicators of motor symptom severity as well as with other measures of NMS, depression and quality of life. Correlations of NMSS items/domains with independent measures of related constructs were weak to moderate. In conclusion, when assessed with the NMSS, a broad range of NMS fluctuate with motor oscillations, but these fluctuations do neither correlate with motor function nor with measures of disease progression.

The effects of rasagiline on olfaction in animal studies are convincing. However, apart from various anecdotal patient reports, they could not be reproduced in prospective studies in humans. Cross-sectional data of large patient groups are still missing. The aim of this study was therefore to determine the olfactory function in a broad heterogeneous Parkinson's disease (PD) population with and without rasagiline intake. In this single-center, cross-sectional study 224 PD patients with and without rasagiline (1 mg/day) participated. Seventy-four of them received rasagiline as mono, or adjunct therapy. One-hundred fifty patients were untreated or received PD medication other than rasagiline. Comprehensive olfactory testing was performed for phenyl-ethyl alcohol odor thresholds, odor discrimination, and odor identification. Olfactory function did not differ between the two treatment groups with disease duration up to 29 years. Rasagiline-treated patients with disease duration of less than 8 years, however, presented with significant better odor discrimination abilities compared to PD patients without rasagiline treatment. This effect was no longer evident in patients with longer disease duration and proofed to be independent of age, sex, and medication. Our results may suggest that rasagiline treatment has a positive effect on the processing of olfactory information in early PD.

Beyond the cardinal motor symptoms, bradykinesia, rigidity, tremor and postural instability, defining the diagnosis of Parkinson's disease, there is a big spectrum of non-motor features that patients may suffer from and that may reduce their quality of life. Non-motor symptoms are not only frequent but also often under-reported by patients and caregivers. As they are frequently under-recognized by clinicians, they remain consequently under-treated. This review wants to give a short overview of the importance of non-motor symptoms on patients' quality of life and helpful assessment tools that might facilitate recognition of non-motor features during clinical setting. Given the wide range of non-motor symptoms in Parkinson's disease, we concentrate on common issues such as depression and sleep disorders like sleep-onset insomnia or sleep maintenance insomnia and restless legs syndrome. Thereby, we present some recent studies that have investigated the efficacy of dopaminergic drugs, especially dopamine agonists, revealing possible treatment strategies and thus improving disease management.

A number of neurodegenerative diseases are associated with iron dyshomeostasis and mitochondrial dysfunction. However, the pathomechanistic interplay between iron and mitochondria varies. This review summarises the physiological role of iron in mitochondria and subsequently exemplifies two neurodegenerative diseases with disturbed iron function in mitochondria: inherited Friedreich ataxia (FRDA) and idiopathic Parkinson disease (PD). In eukaryotes, mitochondria are main consumers of iron. The respiratory chain relies on iron-containing redox systems in the form of complexes I-III with iron-sulphur clusters and cytochromes with haem as prosthetic groups. The bifunctional enzyme aconitase is not only important in the citric acid cycle, but also functions as a key regulator of cell iron metabolism. Haem biosynthesis occurs partially in mitochondria as well as the biogenesis of iron-sulphur clusters that are co-factors in numerous iron-sulphur proteins. FRDA is characterised by a mutation of the frataxin gene, the protein of which serves as an iron chaperone in iron-sulphur cluster assembly. The lack of frataxin expression leads to defective iron-sulphur cluster biogenesis with decreased respiratory and aconitase activity. The resulting mitochondrial iron overload might fuel reactive oxygen species formation and contribute to clinical signs of oxidative stress. PD is typically associated with an increased iron content of the substantia nigra, the causes of which are largely unknown. Recent research demonstrated raised iron levels in individual dopaminergic neurons of the substantia nigra. Moreover, transferrin/transferrin receptor 2 mediated transport of iron into the mitochondria of these neurons was identified together with increased transferrin immunoreactivity. Resulting accumulation of iron into mitochondria might lead to oxidative stress damaging iron-sulphur cluster-containing proteins.

The cold hand sign (CHS) is a distinct feature of multiple system atrophy (MSA), but its pathophysiology is poorly understood. We, therefore, conducted a study to examine the skin temperature and the skin blood flow at rest and after local heating in 6 age-matched MSA patients with CHS (MSA + CHS), 18 MSA patients without CHS (MSA - CHS) and 13 patients with idiopathic Parkinson's disease (PD). Basal skin temperature and blood flow were significantly lower in MSA + CHS patients than in MSA - CHS or PD patients. Local heating induced a greater response in terms of amplitude in MSA + CHS compared to MSA - CHS and PD. Considering kinetics, skin blood flow increment per 1 degrees C was higher in MSA + CHS than MSA - CHS but was similar when compared to PD patients. Skin blood flow rate (change per second) did not differ among the groups. Our findings suggest that despite impaired basal skin perfusion, the skin vasomotor response to local heating is intact in MSA + CHS but disturbed in MSA - CHS. By measuring skin temperature and blood flow, the presence of CHS can be diagnosed in MSA patients. Further studies are necessary to understand regulation of skin perfusion in patients with extrapyramidal disease.

Differential diagnosis of parkinsonian syndromes is a major challenge in movement disorders. Dysautonomia is a common feature but may vary in clinical severity and onset. The study attempted to find a pattern of autonomic abnormalities discriminative for patients with different parkinsonian syndromes. The cross-sectional study included 38 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 26 patients with idiopathic Parkinson's disease (IPD) and 27 age-matched healthy controls. Autonomic symptoms were evaluated by a standardized questionnaire. The performance of patients and controls was compared on five autonomic function tests: deep breathing, Valsalva manoeuvre, tilt-table testing, sympathetic skin response, pupillography, and 24-h ambulatory blood pressure monitoring (ABPM). Disease severity was significantly lower in IPD than PSP and MSA. Except for pupillography, none of the laboratory autonomic tests distinguished one patient group from the other alone or in combination. The same was observed on the questionnaire. Receiver operating characteristic curve revealed discriminating performance of pupil diameter in darkness and nocturnal blood pressure change. The composite score of urogenital and vasomotor domains significantly distinguished MSA from IPD patients but not from PSP. Our study supports the observation that even mild IPD is frequently indistinguishable from more severe MSA and PSP. Thus, clinical combination of motor and non-motor symptoms does not exclusively point at MSA. Pupillography, ABPM and the questionnaire may assist in delineating the three syndromes when applied in combination.

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.

There is an ongoing controversy about potential toxicity of L-3,4-dihydroxyphenylalanine (L-dopa) to dopaminergic neurons in Parkinson's disease (PD). Neuroimaging data suggest that L-dopa accelerates the loss of dopamine nerve terminals, especially at higher doses. The disputed aspect of toxicity and the frequently observed motor complications accompanying L-dopa therapy have led to an increased use of dopamine agonists during the past two decades. Reports describing their neuroprotective potential to dopaminergic neurons have attracted much attention. Here, we describe the novel finding that the combination of a dopamine (DA) agonist, alpha-dihydroergocryptine (DHEC), with L-dopa or DA exerts a synergistic stimulatory effect on dopaminergic neurons in primary culture, while each substance alone had no or less effect. DA receptor stimulation plays a decisive role. The synergistic effect suggests that a combinatory therapy can be beneficial to slow the degeneration of dopaminergic neurons.

Dopamine agonists are an important therapeutic strategy in the treatment of Parkinson's disease. They postpone the necessity for and reduce the required dose of L-3,4-dihydroxyphenylalanine (L-DOPA) medication thus protecting against the development of motor complications and potential oxidative stress due to L-DOPA metabolism. In primary cultures from mouse mesencephalon we show that pergolide, a preferential D(2) agonist enhanced the survival of healthy dopaminergic neurons at low concentrations of 0.001 microM. About 100 fold higher concentrations (0.1 microM) were necessary to partially reverse the toxic effects of 10 microM 1-methyl-4-phenylpyridinium (MPP(+)). Pergolide was equally effective in preventing the reduction of dopamine uptake induced by 200 microM L-DOPA. Furthermore, between 0.001-0.1 microM it also reduced lactate production thus promoting aerobic metabolism. The present findings suggest that pergolide protects dopaminergic neurons under conditions of elevated oxidative stress.

Dopamine agonists play an important role in the treatment of Parkinson's disease by reducing the administration of L-3,4-dihydroxyphenylalanine (L-DOPA). The enzymatic and non-enzymatic conversion of L-DOPA is suspected to increase oxidative stress, which leads to the degeneration of dopaminergic neurons in Parkinson's disease. In primary mouse mesencephalic cultures we show that the dopamine D1/D2 receptor agonist lisuride, in a concentration range of 0.001–1 μM, enhances the survival of dopaminergic neurons, protects against toxicity induced by L-DOPA or 1-methyl-4-phenylpyridinium ion (MPP+) and stimulates 3H-dopamine up-take. Lisuride also reduces anaerobic metabolism during incubation with L-DOPA. The present findings suggest that lisuride may have trophic/survival-promoting properties and potentially reduces oxidative stress.

Ropinirole is effective as mono- and combination therapy in PD. Previous studies have used a maximal dose of 24 mg/day; the present study assesses the effect of higher doses (up to 36 mg/day) on patients with motor fluctuations. Outcome measures were changes in the motor function score of the Unified Parkinson's Disease Rating Scale, the duration of dyskinesias and reductions in levodopa dose. 21/22 patients completed the study. The mean daily ropinirole dose at endpoint was 26.2 mg (SD, 4.43 mg, range 20-36 mg). Improvements in motor function (29%) and the duration of dyskinesias (45%) from baseline to endpoint were significant (p < 0.01 and p < 0.05, respectively). The mean levodopa dose fell by 32% during the study (from 599 mg to 409 mg; p = 0.007). Side effects were mild. High-dose ropinirole (20-36 mg/day) was well tolerated and conferred significant clinical benefit on patients with motor fluctuations.

Human cerebrospinal fluid (CSF) contains chromogranin A and B and secretogranin II which represent peptides secreted from neuronal large dense core vesicles. Within these vesicles these precursor peptides are at least partly processed to smaller peptides. We analysed the CSF levels of chromogranins/secretogranin by radioimmunoassay using specific antisera. The degree of their processing was characterized by molecular sieve column chromatography followed by radioimmunoassay. As previously shown secretogranin II is fully processed to smaller peptides including the peptide secretoneurin, whereas processing of chromogranin A was more limited. For chromogranin B we found in this study a high degree of processing comparable to that of secretogranin II. An analysis of CSF from patients with multiple sclerosis, essential tremor, Alzheimer and Parkinson disease, did not reveal any differences in proteolytic processing of chromogranins/secretogranin when compared to control CSF. We conclude that in the four diseases investigated there is no change in the proteolytic processing of the chromogranins/secretogranin within the large dense core vesicles. The absolute levels of chromogranins/secretogranin varied in CSF collected in different hospitals, however their relative ratios were remarkable constant. We suggest to use this ratio as a parameter to standardise CSF levels of other peptides, e.g. neuropeptides. In Parkinson patients the chromogranin A/secretogranin II ratio was significantly increased whereas in Alzheimer patients and those with essential tremor and multiple sclerosis no change of the ratios was observed. Apparently there are only limited changes in the biosynthesis, processing, secretion and CSF clearance of these peptides in pathological conditions.

The present study aimed at relating dementia, pseudo-neurasthenic and affective organic brain syndromes to underlying type of CSF flow disorder and to subsequent alteration of anatomy. T2*-weighted magnetic resonance imaging (MRI) in the midsagittal plane permitted an analysis of aqueductal CSF flow phenomena and hydrocephalus-induced elevation, thinning and dorsal impingement of the corpus callosum. Furthermore, the width of the third ventricle was measured on the transverse scout images. 72 patients with communicating hydrocephalus (increased aqueductal CSF pulsations) and 26 patients with aqueductal stenosis (absence of aqueductal flow phenomena) were compared with 22 controls. Dementia and affective disorders were distributed equally among both CSF flow subgroups whereas pseudo-neurasthenic syndromes were observed more frequently in non-communicating hydrocephalus (p < 0.03). Alzheimer-type and multiinfarct dementia syndromes were found more frequently in communicating hydrocephalus whereas non-classifiable dementia showed some predilection for non-communicating hydrocephalus. Callosal height, area and third ventricular width did not predict affective or pseudoneurasthenic disorder whereas third ventricular width (p < 0.01) and callosal area (p < 0.05) discriminated between demented and non-demented patients. Dorsal impingement of the corpus callosum by the falx was a non-specific finding.

In this Supplement of the Journal of Neural Transmission, we address an important feature of Parkinson’s syndrome, i.e. nocturnal problems. We feel very honoured that so many eminent experts in this field have contributed to a supplement which should be of interest to everyone who deals with Parkinson’s disease (PD). It is accepted by neuroscientists that PD is a progressive disease with an accumulation of a-synuclein (Spillantini et al. 1997). Since these accumulations are also found in the mesencephalon where sleep regulation is located, it follows that impairment of sleep is a natural consequence of this progressive disease (Braak et al. 2003). Even James Parkinson addressed sleep problems in his essay on the shaking palsy when he writes ‘‘...as the malady proceeds, the sleep becomes much disturbed...’’ (Parkinson 1817). REM sleep behaviour disorder (RBD) is associated with hyposmia, constipation and depression as among the most frequent and important pre-motor symptoms in PD (Bhidayasiri and Reichmann 2013; Reichmann 2010). Patients with RBD lack physiological atonia during REM sleep and frequently scream and move violently, often injuring their sleeping partners. More than 60 % of these patients will later develop a second neurodegenerative disorder, very often PD or atypical parkinsonism (Claassen et al. 2010). But there are many more nocturnal disturbances in patients with PD such as nocturia, pollakisuria, problems falling asleep, problems staying asleep, restless legs syndrome, pain during nighttime, early morning akinesia and many more (Grandas and Iranzo 2004). Patients rate nighttime problems rather high when they are asked what impairs their quality of life the most (Barone et al. 2009). Thus, it is obvious that we need scales to quantify these features. Fortunately, such scales have been developed which give a good estimate of sleep problems in PD (Hogl et al. 2010). For others we can use the Parkinson’s disease sleep scale (PDSS) or the scales for outcomes in PD sleep (SCOPA-S) (Chaudhuri et al. 2002; Marinus et al. 2003). Of all nonmotor symptoms in PD, sleep problems belong to the most serious ones since they do not only impair quality of sleep and rest but also impair motor performance in the early morning and give rise to fatigue and somnolence during daytime (Comella 2006). Both nighttime and daytime problems also impair the quality of life of the patients’ caregivers since they do not find enough rest to take care of the patients during the daytime (Martinez-Martin et al. 2007). Thus, treatment of nocturnal problems in PD is extremely important. Most PD specialists use a long-acting dopamine replacement therapy to address a dopaminergic trough during the nighttime (Ray Chaudhuri et al. 2012; Trenkwalder et al. 2011). It is helpful to use extendedrelease preparations of levodopa since there would not be any interference with food at nighttime (Chouza et al. 1990). Long-acting dopamine agonists are extremely helpful to overcome nighttime problems and to increase the possibility of a good start of the next day. In addition, the H. Reichmann Klinik und Poliklinik fur Neurologie, Universitatsklinikum Carl Gustav Carus, Dresden, Germany

The field of Parkinson’s disease is quite dynamic. For one century and a half, it was considered to be almost exclusively a movement disorder, while non-motor features have received meager if any attention. The first meetings specifically highlighting these forgotten areas were held in 1993 in Amsterdam and Jerusalem, and they paved the way to an astonishing expansion in the field. The present volume includes selected presentations from the Eighth International Congress on Mental Dysfunctions and other non-motor features in Parkinson’s disease and related disorders which took place in Berlin with over 800 participants. The topics, as seen in this volume, extended across the field to include mental, autonomic, sensory, and other manifestations, in Parkinson’s disease as well as other movement disorders, with emphasis on the diagnosis and therapy. Following the success of the 2013 Congress in Seoul, the next meeting, the Tenth International Congress on Mental Dysfunctions and other non-motor features in Parkinson’s disease and related disorders will take place in Nice, France, on 4–7 December 2014, with an exciting new program. We hope to see many of you there.

Levodopa/Carbidopa, respectively, Levodopa/Benserazide is the most effective treatment for Parkinson's disease and during the progress of the disease, patients will inevitably need to be treated with it. Nonetheless, after a certain time period most of the patients experience side effects. Mainly disturbing are motor and non-motor fluctuations and dyskinesia. Numerous options from changing the medication regimen, to continuos dopaminergic drug delivery via apomorphine or Duodopa pumps and stereotactical interventions are available. The physician's responsibility is to choose the right therapeutic procedure for each timepoint of the patient's disease. In this review, we provide an up to date overview of the available strategies.