Andrea Pilotto

Pharmacological Strategies for the Management of Levodopa- Induced Dyskinesia in Patients with Parkinson's Disease

Abstractl-Dopa-induced dyskinesias (LID) are the most common adverse effects of long-term dopaminergic therapy in Parkinson’s disease (PD). However, the exact mechanisms underlying dyskinesia are still unclear. For a long time, nigrostriatal degeneration and pulsatile stimulation of striatal postsynaptic receptors have been highlighted as the key factors for the development of LID. In recent years, PD models have revealed a wide range of non-dopaminergic neurotransmitter systems involved in pre- and postsynaptic changes and thereby contributing to the pathophysiology of LID. In the current review, we focus on therapeutic LID targets, mainly based on agents acting on dopaminergic, glutamatergic, serotoninergic, adrenergic, and cholinergic systems. Despite a large number of clinical trials, currently only amantadine and, to a lesser extent, clozapine are being used as effective strategies in the treatment of LID in clinical settings. Thus, in the second part of the article, we review the placebo-controlled trials on LID treatment in order to disentangle the changing scenario of drug development. Promising results include the extension of l-dopa action without inducing LID of the novel monoamine oxidase B- and glutamate-release inhibitor safinamide; however, this had no obvious effect on existing LID. Others, like the metabotropic glutamate-receptor antagonist AFQ056, showed promising results in some of the studies; however, confirmation is still lacking. Thus, to date, strategies of continuous dopaminergic stimulation seem the most promising to prevent or ameliorate LID. The success of future therapeutic strategies once moderate to severe LID occur will depend on the translation from preclinical experimental models into clinical practice in a bidirectional process.

Developments in the Role of Transcranial Sonography for the Differential Diagnosis of Parkinsonism

In the last two decades transcranial sonography (TCS) has developed as a valuable, supplementary tool in the diagnosis and differential diagnosis of movement disorders. In this review, we highlight recent evidence supporting TCS as a reliable method in the differential diagnosis of parkinsonism, combining substantia nigra (SN), basal ganglia and ventricular system findings. Moreover, several studies support SN hyperechogenicity as one of most important risk factors for Parkinson’s disease (PD). The advantages of TCS include short investigation time, low cost and lack of radiation. Principal limitations are still the dependency on the bone window and operator experience. New automated algorithms may reduce the role of investigator skill in the assessment and interpretation, increasing TCS diagnostic reliability. Based on the convincing evidence available, the EFNS accredited the method of TCS a level A recommendation for supporting the diagnosis of PD and its differential diagnosis from secondary and atypical parkinsonism. An increasing number of training programmes is extending the use of this technique in clinical practice.

Application of the movement disorder society prodromal Parkinson's disease research criteria in 2 independent prospective cohorts: Application of Research Criteria For Prodromal PD

Background: The research criteria for prodromal PD of the MDS propose a new approach for the assessment of the individual probability of prodromal PD. These criteria require a testing of their reliability in different prospective cohorts.

Erratum: Structural Ultrasound of the Medial Temporal Lobe in Alzheimer’s Disease

Purpose One of the anatomical hallmarks of Alzheimer’s disease (AD) is the atrophy of the medial temporal lobe (MTL), yet cost-effective and broadly available methodological alternatives to the current imaging tools for screening of this brain area are not currently available. Materials and Methods Using structural transcranial ultrasound (TCS), we attempted to visualize and measure the MTL, and compared the results of 32 AD patients and 84 healthy controls (HC). The MTL and the surrounding space were defined in the coronal plane on TCS. A ratio of the height of the MTL/height of the choroidal fissure (M/F) was calculated in order to obtain a regional proportion. Results An insufficient temporal bone window was identified in 22 % of the AD patients and 12 % of the HCs. The results showed that the ratio of M/F was significantly smaller in the AD group on both sides (p = 0.004 right, p = 0.007 left side). Furthermore, the M/F ratio made it possible to discriminate AD patients from HCs with a sensitivity of 83 % (right)/73 % (left) and a specificity of 76 % (right)/72 % (left) which is basically comparable to results published for magnetic resonance imaging. The measurements showed substantial intra/interrater reliability (ICC:0.79/0.69). Conclusion These results suggest that utilization of structural TCS may possibly constitute a cheap and easy-to-use supplement to other techniques for the diagnosis of AD. It may be especially useful as a screening tool in the large population of individuals with cognitive decline. Further studies are needed to validate this novel method.

Microarray Gene and miRNA Expression Studies: Looking for New Therapeutic Targets for Frontotemporal Lobar Degeneration

Preclinical Research

GBA-associated parkinsonism and dementia: beyond α-synucleinopathies?

To date the role of GBA mutations beyond α‐synucleinopathies in the parkinsonism−dementia spectrum is still unclear. The aim of the study was to screen for GBA mutations in progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), primary progressive aphasia (PPA) and the behavioural variant of frontotemporal dementia (bvFTD).

In vivo markers of Parkinson’s disease and dementia with Lewy bodies: current value of the 5G4 α-synuclein antibody

additional 35 kDa band on immunoblotting was found only in individuals with DLB. In another recent report, the same group detected a trend towards higher cerebrospinal fluid (CSF) 5G4 α-synuclein levels in four out of seven patients affected by α-synucleinopathies [7]. We tested the same 5G4-Ab for the first time in a large series of living patients (PATHO-Kit, Analytic Jena Roboscreen GmbH, Leipzig, Germany). The study evaluated serum 5G4 and total α-synuclein levels (MONO-kit, same company) in patients with a diagnosis of PD [n = 130, 31 with dementia (PDD)] and DLB (n = 36) according to current clinical criteria (Supplementary material). In the serum, mean 5G4 α-synuclein levels were similar in PD, DLB and healthy controls (n = 101) (Table 1). Total α-synuclein levels were lower in DLB compared to controls (p = 0.001), while the total/5G4α-synuclein ratio was similar in all groups. Separate analysis of outliers did not show relevant associations between the marker and demographic, clinical and neurochemical routine parameters (Supplementary Table 1). The only remarkable finding was an earlier age at Despite the great advances in understanding the molecular mechanisms involved in α-synucleinopathies, translational research is still looking for a reliable in vivo biomarker. As an important step forward in this field, Kovacs et al. [1] published in this Journal in 2012 the isolation of a new monoclonal antibody (5G4-Ab) specific for accumulated misfolded (but not physiological monomeric) α-synuclein, which was found after generation of α-synuclein aggregates by mice immunization. This antibody was tested in comparative immunohistochemical studies in brain tissue of patients with Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). 5G4-Ab showed higher sensitivity and specificity compared to available immunohistochemical assays. An

Cognitive impairment in Glucocerebrosidase (GBA)‐associated PD: Not primarily associated with cerebrospinal fluid Abeta and Tau profiles

A proportion of idiopathic Parkinsons disease patients (PDidiopathic) with dementia show altered CSF profiles of amyloid β (Aβ) and Tau. PD patients with Glucocerebrosidase (GBA) mutations (PDGBA) present with even more cognitive decline than seen in PDidiopathic.