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Purpose Given the fact that retina may provide a window into the central nervous system, there has been interest in identifying retinal biomarkers as predicting factors of pathological processes in neurodegenerative disorders. Emerging evidence has suggested that macular microcirculation changes in Parkinson disease (PD) may indicate the alterations of cerebral microvasculature. The use of Optical Coherence Tomography Angiography (OCT-A) has attracted significant attention in recent years as this technique offers a detailed analysis of the existence of changes at the macular capillary plexus. Methods A detailed review of the literature was performed in PubMed until June 2021. We identified all papers referring to the alterations of the macular capillary plexus in PD using OCT-A. Results A comprehensive update indicates that microvasculature alterations of the macular capillary plexus utilizing OCT-A may comprise useful biomarkers regarding the cerebral vasculature in PD. Since the available evidence is limited, additional studies are warranted to establish the OCT-A parameters as predicting factors in clinical practice. Conclusions A review of the existing literature sheds light on the microvasculature changes of the macular capillary plexus as seen on OCT-A in PD patients. The current article discusses notable aspects of key publications on the topic, highlights the importance of the potential long-term effectiveness of OCT-A biomarkers in PD and proposes the need for further future research.

The advent of next generation sequencing has revolutionized diagnostic approaches to hereditary polyneuropathies. Recently, mutations on the membrane metallo-endopeptidase (MME) gene, encoding neprilysin, have been related to the development of late-onset Charcot-Marie-Tooth disease type 2 (CMT2). Here, we report the first Greek patient presenting with a slowly progressive late-onset axonal polyneuropathy and a novel, likely pathogenic, heterozygous variant in the MME gene. In addition, we have performed a systematic review of all published case reports of patients with MME mutations. The results of the studies show that MME variants can be inherited as both fully penetrant autosomal-recessive and incompletely penetrant autosomal-dominant traits. A number of heterozygous variants characterized as incompletely penetrant impose an increased risk of developing a CMT2-like phenotype late in life, identical to the case study described here. Greater mutation numbers in different populations and mutation-specific functional studies will be essential to identify the pathogenicity and inheritance of more MME variants.

Background: The Parkinson’s Disease-Cognitive Rating Scale (PD-CRS) is a comprehensive screening procedure for the evaluation of cognitive impairment in patients with Parkinson’s disease (PD). Objectives: In the present study we adjusted the PD-CRS for the Greek population, developed normative data and examined its clinical utility for the assessment of cognitive functioning in Greek PD patients. In addition, the correlation of clinical characteristics with cognitive performance in PD patients was examined. Methods: Three hundred four community-dwelling healthy adults and 59 patients with PD, completed the adapted PD-CRS. Results: Healthy adults outperformed the PD patients on the total, the cortical and subcortical scores of the PD-CRS. Normative data indicated effects of both education and age on the PD-CRS. The optimal total PD-CRS cutoff score for the identification of cognitive impairment in a heterogeneous sample of PD patients, with regard to the severity of cognitive difficulties, was 79, yielding a modest sensitivity and specificity. Clinical characteristics of the patients (i.e., disease duration and functional disease burden) were related to poor performance on the PD-CRS. Conclusions: The Greek version of the PD-CRS is a useful instrument for the assessment of cognition in PD. Future prospective studies should examine its clinical utility to identify PD-cognitive subtypes (i.e., PD patients with mild cognitive impairment), to monitor cognitive changes, as well as its predictive accuracy for subsequent dementia.

Absence seizures are expressed with distinctive spike-and-wave complexes in the electroencephalogram (EEG), which can be used to automatically distinguish them from other types of seizures and interictal activity. Considering the chaotic nature of the EEG signal, it is very unlikely that such continuous, repetitive patterns with strict periodic behavior would occur naturally under normal conditions. Searching for spectral activity in the range of 2.5-4.5 Hz and assessing the presence of synchronous, repeated patterns across multiple EEG channels in an unsupervised manner, the proposed methodology provides high absence seizure detection sensitivity of 93.94% with a low false detection rate of 0.168 FD/h using the open TUSZ dataset.

The purpose of the present study was to investigate the pattern of white matter (WM) changes associated with Parkinson's disease (PD)-related cognitive impairment by using fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) measures. Diffusion Tensor Imaging (DTI) was performed in 21 PD-patients with dementia (PDD) and in an age-matched control group including 40 PD-patients without dementia (PD-CTRL). The Parkinson's disease-Cognitive Rating Scale (PD-CRS) was used for patients' neuropsychological assessment. Local microstructural WM differences associated with the presence of cognitive impairment were tested using tract-based spatial statistics analysis. Multiple regression models investigated the association of DTI indices with total PD-CRS score, PD-CRS raw items and other clinical measures across the whole study sample. Significant FA decreases were found in PDD compared to PD-CTRL patients mainly in the body of corpus callosum, corona radiata and cingulum. Lower PD-CRS score was significantly associated with decreased FA, MD and AD values in multiple WM tracts primarily located in prefrontal and limbic areas as well as across the corpus callosum. Lower performance in specific PD-CRS raw items was also associated with FA decreases in major WM tracts. The results suggest that multifocal microstructural changes of WM accompany the transition from normal to demented cognitive state in PD-patients. The corpus callosum, the corona radiata and the cingulum are among the regions mostly affected during this course. A progressive axonal degeneration is proposed as a key underlying mechanism.

Purpose: To present an unusual case of posterior encephalopathy syndrome (PRES) preceded by intracranial hypotension.Materials and Methods: We present a case of a 27-year-old parturient with an uneventful pregnancy that shortly after labor developed a persistent headache with characteristics compatible with intracranial hypotension. The patient had undergone epidural anesthesia for caesarian section. Results: The symptomatology of intracranial hypotension was attributed to inadvertent dural puncture during epidural anesthesia. The MRI revealed multiple white matter lesions located in frontal, temporal and parietal regions of both hemispheres. The type of lesions was suggestive of PRES. Pachymeningeal enhancement was also observed. The patient was managed conservatively. The symptoms improved gradually and the imaging findings resolved completely. Conclusions: This case demonstrates the need for clinical alertness for PRES in patients with prolonged and possibly atypical symptoms of intracranial hypotension. As probable causal relationship between these disorders we propose a sympathetic over-activation as a result of cerebrospinal fluid leakage leading to vasospasm and manifestation of PRES.

Objectives The purpose of this study was to generate normative data on the Symbol Digits Modalities Test (SDMT) for the written and oral versions in the Greek adult population. We also investigated the test’s validity in discriminating the performance of healthy adults from two groups of adults diagnosed with relapsing remitting (RRMS) and secondary progressive (SPMS) multiple sclerosis. Method The sample consisted of 609 healthy men and women between the ages of 18 and 65. All participants were monolingual native Greek adult speakers. Each healthy participant was administered either the written (n = 460) or oral (n = 149) versions of the SDMT. Discriminant validity was examined by comparing 35 healthy participants who had completed the oral version of the SDMT to 35 age - and education-matched RRMS and SPMS patients. Results Linear regression models explained between 36% and 55% of the variance in the SDMT oral and written version scores. Age was the strongest predictor of difference in SDMT written and oral version performance, followed by education that also accounted for a further proportion of the SDMT variance. On the contrary, gender was found not to contribute significantly to the variance in the SDMT for either the written or the oral versions. As a result, age- and education-adjusted norms were generated. Regarding the tests discriminative validity, we found that both MS patient groups scored significantly lower than the healthy group. Conclusions This is the first study to provide comprehensive normative data for the SDMT in the adult population in Greece, impacting the future practice of neuropsychological assessment in this country.

The aim of this work is to present the architecture of the ProMiSi tool, a software for the analysis of magnetic resonance imaging and the extraction of information on the progression of multiple sclerosis disease. ProMiSi is based on the automatic processing, segmentation and post-processing of MRI for the automatic labeling, visualization and volumetric quantification of segmentable brain structures from magnetic resonance image. The combination of the above mentioned volumetric results with other type of information (e.g. clinical, demographic etc.), through autonomous learning intelligent techniques, allows the evaluation of the severity and the progress prediction of the multiple sclerosis and consequently the personalized management of the disease. A proof of concept study with 30 patients will take place for the validation of the algorithms, while ProMiSi will be evaluated in terms of functionality, usability, reliability, performance and supportability.

The multimodal imaging investigation of excessive daytime sleepiness (EDS) in Parkinson's disease (PD). The role of dopaminergic treatment and other clinical parameters was also evaluated.Seventeen non-demented PD patients with EDS (PD-EDS) and 17 PD patients without EDS were enrolled. Clinical, treatment and MRI data were acquired. Gray matter (GM) volume was examined with voxel-based morphometry, while white matter (WM) integrity was assessed with diffusion tensor imaging by means of fractional anisotropy, mean diffusivity, axial diffusivity (AD) and radial diffusivity measures.Increased regional GM volume was found in the PD-EDS group bilaterally in the hippocampus and parahippocampal gyri. Increased AD values were also shown in the PD-EDS group, in the left anterior thalamic radiation and the corticospinal tract and bilaterally in the superior corona radiata and the superior longitudinal fasciculus. Levodopa equivalent dose differed significantly between the groups and was the only predictor of EDS, while the only predictor of the Epworth sleepiness scale score in the PD-EDS group was the dopamine-agonist dose. Increased frequency of gamblers was also observed in the PD-EDS group.Regional GM increases and increased AD values in certain WM tracts were found in the PD-EDS group. The changes could result from disinhibited signaling pathways or represent compensatory changes in response to anatomical or functional deficits elsewhere. The study findings support also the contribution of the total dopaminergic load in the development of EDS, while the dose of dopamine agonists was found to predict the severity of the disorder.

We investigated whether there is a linear relationship between levodopa (LD) dose and treatment duration, and the development of levodopa-induced dyskinesia (LID) among patients with early untreated Parkinson’s disease (PD). We performed a meta-analysis of randomized-controlled trials (RCTs) comparing LD monotherapy to any other antiparkinsonian treatment in early PD patients. Meta-regressions were conducted including as covariates the effects of LD dose, treatment duration, and age. We further proceeded in subgroup analyses based on the type of medications in the non-LD monotherapy (control) group and on whether patients in the control group received additional levodopa or not. Thirteen eligible RCTs were included, which revealed a significantly higher risk for dyskinesia in patients initially treated with LD monotherapy compared to any other treatment (OR = 2.82). None of the subsequent meta-regressions revealed any significant relationship with dose, treatment duration or age. Patients treated on LD monotherapy or MAOΙ plus LD were at a greater risk to develop LID than patients who received DA only or DA plus supplemental LD. The increased heterogeneity compromised the robustness of the results. The alleged correlation between LID and LD dose and treatment duration cannot be verified based on the data available so far. Well-designed, large-scale, long-term, RCTs on drug-naive PD patients could allow the better comprehension of the pattern of the association between LID and LD treatment parameters.

Parkinson's disease is a neurodegenerative disease, with a constantly increasing prevalence and a high global financial impact arising from direct and indirect costs. Large-scale, observational studies provide data that support the better comprehension of disease aspects, constitute a baseline reference for future studies and assist comparisons among different patient populations, allowing the recognition of distinctive characteristics and special needs. The present study is the first to depict the clinical characteristics and their interplay in a large sample of Parkinson's disease (PD) patients in Greece. Nine hundred eighty six consecutive PD outpatients were recruited from 17 centers around Greece in the time period from 8/2007 to 7/2009 and were examined and interviewed by movement disorders experts. Multiple clinical characteristics were recorded including age at diagnosis, disease severity, patients' self classification of PD symptoms and their relevance to physician's global clinical impression, smoking, alcohol consumption, presence of family history for PD, dementia, depression, hypertension, cancer and other comorbidities. Associations of high clinical significance were found between certain clinical characteristics.

The ALZCARE project aims at assisting people at risk or already suffering of dementia, their family and health professionals in the dementia care pathway by providing an integrated ICT-enabled information System. The system consists of a mobile platform for screening people at risk, a Clinical Information System and a satellite-based patient tracking system. The system is currently on the evaluation phase focusing on addressing the needs of citizens of the cross-border areas of Greece and Albania.

Long-term levodopa replacement therapy in Parkinson's disease is confounded by abnormal involuntary movements, known as levodopa induced dyskinesia (LID). Dysfunctional glutamatergic neurotransmission has been implicated in the pathogenesis of LID making metabotropic and ionotropic glutamate receptors attractive novel therapeutic targets. The objective of the present study was to investigate the antidyskinetic site of action of different glutamate receptor antagonists in the brain. For that purpose, metabotropic glutamate subtype 5 (3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride, MTEP), NMDA NR2B selective ((aR,bS)-a-(4-Hydroxyphenyl)-b-methyl-4-(phenylmethyl)-1-piperidinepropanol maleate, Ro 25-6981) and AMPA (2,3-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt, NBQX) receptor antagonists or saline were administered by intracerebral infusion in the caudate-putamen (CPu), the substantia nigra zona reticulata (SNr) or the subthalamic nucleus (STN) of 6-hydroxydopamine-lesioned rats exhibiting LID. Dyskinesia was assessed with the modified version of the rat Abnormal Involuntary Movements scale (AIMS). Ro 25-6981 and to a lesser extent NBQX improved dyskinesia (82% and 19% reduction in AIM score respectively) after infusion in the caudate-putamen. None of the three drugs managed to noticeably reduce AIM score after infusion in the SNr. MTEP was the only drug that produced a reduction in AIM score (48%) when infused in STN. In conclusion, while the striatum proved important in the antidyskinetic action of NMDA and AMPA receptor antagonists, the results of this study highlight also the importance of the metabotropic glutamate receptors that reside in the STN as therapeutic targets in the treatment of LID. Eur J Pharmacol

The efficacy and safety of levetiracetam (LEV), administered for management of levodopa-induced dyskinesias (LID) in Parkinson's disease (PD), was examined using a multicenter, double-blind, placebo-controlled, parallel groups, crossover trial. Because of having a period effect, data after crossover point was excluded from analysis. Levodopa-treated PD participants with LID (n = 38) received LEV 500 mg/day, were assessed, titrated to 1,000 mg/day and reassessed, before and after crossover. The placebo group followed the same routine. Primary efficacy was defined from percent change in "On with LID" time from patient diaries. Secondary efficacy assessment used "On without LID," "Off" time, unified PD rating scale (UPDRS), clinical global impression (CGI), and Goetz dyskinesia scale after levodopa challenge. Safety measures were also performed. On with LID time decreased 37 minutes (95% confidence interval [CI] 0.59, 7.15; P = 0.02) at 500 mg/day, 7.85% 75 minutes (95% CI 3.3, 12.4; P = 0.002) at 1,000 mg/day. On without LID time increased by 46 minutes (95% CI -1.55, -0.03; P = 0.04) at 500 mg/day and 55 minutes (95% CI -10.39, -1.14; P = 0.018) at 1,000 mg/day. UPDRS 32 showed decreased dyskinesia duration mean change 0.35 (95% CI 0.09, 0.5; P = 0.009) at 1,000 mg/day. CGI showed LID decreased by 0.7 (95% CI 0.21, 1.18; P = 0.006) at 1,000 mg/day. Patient diaries and UPDRS show no increase in Off time. This exploratory trial provides evidence that LEV in 1,000 mg/day, slowly titrated, could be useful in improving LID as was assessed with patient diaries, UPDRS, and CGI scales, safely, with minimal side effects.

The aim of the present study was to investigate the course of levodopa induced dyskinesia (LID) development in parkinsonian rats treated with several different levodopa dosing regiments. Administration of 6.25 mg/kg levodopa once daily did not induce any dyskinesia for the first 12.5 ± 2.5 days. Then, LID gradually increased in intensity reaching an AIMs score on day 40 of 6.3 ± 0.9. Treatment with 6.25 mg/kg of levodopa qid resulted in the rapid appearance of LID with a mean latency of 2 days and an AIMs score of 19.9 ± 2.9 on day 10. Levodopa (25 mg/kg) once daily induced severe LID from the second day of treatment reaching an AIMs score of 35 ± 3.2. In summary, the worst way for delivering levodopa was through intermittent administration of high doses. The daily cumulative dose of levodopa was found more important for LID induction than the total amount of levodopa received. In contrast, the best way to administer levodopa in respect to prevention/delay of LID was “low dopaminergic stimulation” with one low daily dose, instead of trying to achieve “continuous dopaminergic stimulation” using several levodopa doses throughout the day. The benefits of this strategy offered protection against severe dyskinesia even if subsequently subjects were switched to high dose levodopa. © 2007 Movement Disorder Society

Chronic daily administration of 6.25mg/kg of levodopa in unilaterally 6-OHDA lesioned rats did not induce any observable behavioral effects for the first 12.5+/-2.5 days. Thereafter, levodopa administration induced abnormal involuntary movements (AIMs), involving the contralateral limb, head, neck and trunk, along with the development of contralateral rotations. AIMs and rotations followed a progressively worsening, highly correlated, parallel course. We suggest that rotational behavior does not represent a pure antiparkinsonian response, but along with levodopa-induced dyskinesia is part of the levodopa-induced motor response complications syndrome. Behav Brain Res

RATIONALE: Tardive dyskinesia is a syndrome of abnormal, involuntary movements, which occurs as a complication of long-term neuroleptic therapy. The pathophysiology of this potentially irreversible syndrome is still an enigma. OBJECTIVE: The objective of the present study was to elucidate the role of N-methyl-D-aspartate (NMDA) receptor involvement in neuroleptic-induced orofacial dyskinesia in rats. METHODS: Animals chronically treated with haloperidol for a period of 40 weeks exhibited significantly more vacuous chewing movements (VCMs), as compared to vehicle-treated controls. In a series of acute experiments, rats received: amantadine (10, 20, and 40 mg/kg i.p.), a low-affinity, uncompetitive NMDA-receptor antagonist (open channel blocker); dextrorphan (5, 10, and 20 mg/kg i.p.), an NMDA receptor channel antagonist; ifenprodil (2.5, 5, and 10 mg/kg i.p.), a noncompetitive allosteric NMDA receptor antagonist acting at the polyamine site; and Ro 25-6981 (2.5, 5, and 10 mg/kg i.p.), a potent and selective blocker of NMDA receptors which contain the NR2B subunit. RESULTS: All the drugs tested, except dextrorphan, reduced VCMs and tongue protrusions with varying efficacies and side effects profiles. Ro 25-6981 was found significantly more potent than amantadine and ifenprodil in reducing VCMs and tongue protrusions at all doses tested, and at the higher dose, it completely eliminated orofacial dyskinesia (p

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and is manifested as a movement disorder. A positive family history is the second most important risk factor for developing the illness, after age. Both autosomal dominant and recessive forms of the illness have been described. Recently deletions in a novel gene, parkin, have been associated with the autosomal recessive form of the illness in Japanese families. In this study, we demonstrate that deletions of exons 5, 6 and 7 of the parkin gene are present in two affected individuals of a Greek pedigree with early onset Parkinson's disease. However, no deletions were identified in a different branch of the same pedigree with three affected individuals. These results suggest that deletions in the parkin gene will be found in other families besides those of Japanese origin and that there must be at least one additional locus responsible for early onset autosomal recessive Parkinson's disease. Hum Genet

Dyskinesias are common, often disabling motor complications emerging in Parkinson's disease following chronic levodopa treatment. Common views associate the development of dyskinesias both with progressive loss of striatal dopamine nerve terminals and with intermittent delivery of the short half-life levodopa. Thus, according to continuous dopaminergic stimulation theory, dopamine agonists having half-lifes longer than levodopa would minimize the risk of the development of dyskinesias. The article highlights some interesting aspects of the clinical trials testing dopamine agonists monotherapy as a strategy that can reduce the risk of motor complications, and raises some concerns in terms of their early use in Parkinson's disease treatment to prevent or delay dyskinesia. Finally, we emphasize the need for reconsideration of arguments against use of levodopa as a starting therapy for Parkinson's disease.

OBJECTIVE: The objective of the study was to demonstrate whether the N-methyl-D-aspartate antagonist, amantadine, can safely ameliorate tardive dyskinesia (TD) without deteriorating the mental state of the patients. METHODS: Twenty-two TD patients, with a mean age 52 years, participated in the study. A double-blind, placebo-controlled, crossover design was used. Patients were randomly assigned to receive either amantadine or placebo for 2 weeks followed by a washout period of 4 days. Subsequently,the groups were crossed over, and the procedure repeated. Participants received amantadine (100 mg) or placebo. Tardive dyskinesia was assessed by means of the Abnormal Involuntary Movements Scale(AIMS). The primary efficacy end point was changes in AIMS score, at baseline and at the end of the 2-week treatment period.Results: After amantadine treatment, patients exhibited a reduced average score of total AIMS (from 13.5 before treatment to 10.5 after treatment,P = 0.000), of facial and oral AIMS (from 5.5 before treatment to 4.2 after treatment, P = 0.002), of extremity AIMS (from 4.18 before treatment to 2.8 after treatment, P = 0.000), and of severity AIMS (from 2.04 before treatment to 1.54 after treatment, P = 0.002). With amantadine,the average total AIMS reduction was 21.81%. On the contrary with placebo treatment, no reduction was noted.In addition, amantadine administration exhibited a positive effect,which was statistically significant for incapacitation and Clinical Global Impression score. Amantadine did not alter any of the cognitive measures used in this study, as Mini-Mental State Examination, distress, and Brief Psychiatric Rating Scale. CONCLUSIONS: Amantadine may be an effective and safe treatment for TD. The severity of TD movements in patients receiving amantadine improved significantly more than in those receiving placebo, as measured by the AIMS score. Clin Neuropharmacol

Naive rats were challenged systematically with apomorphine after receiving unilateral dorsal or ventral intracaudate injections of the dopamine D-1 receptor antagonist, SCH23390, or the D-2 receptor antagonist, sulpiride. Sulpiride injections into both the dorsal and ventral striatum induced a robust ipsilateral rotation, while SCH23390 elicited a weaker ipsilateral rotation only on injection into the ventral striatum. Both drugs were ineffective in saline-treated rats, although sulpiride injections into the ventral striatum after systemic saline elicited a small ipsilateral preference. The results from this rotational model mediated by normosensitive receptors indicate that only dopamine D-1 receptors in the ventral striatum mediate rotation while D-2 receptors in both striatal regions mediate rotation. A functional dichotomy between these two neostriatal regions is thus proposed. Eur J Pharmacol

The objective of the study was to determine the safety and efficacy of increasing doses of Rotigotine CDS in patients with advanced Parkinson's disease. The development of motor complications in Parkinson's disease has been linked to intermittent stimulation of dopamine receptors. Continuous, noninvasive, dopaminergic stimulation has not been available to date. Rotigotine CDS is a lipid-soluble D2 dopamine agonist in a transdermal delivery system that could fill this void. This inpatient study consisted of a 2-week dose escalation phase followed by a 2-week dose maintenance phase at the highest dose (80 cm2). Each individual's L-Dopa dose was back-titrated as feasible. The primary outcome measure was L-Dopa dose, and secondary outcome measures included early morning "off"-L-Dopa Unified Parkinson's Disease Rating Scale motor scores by a blinded evaluator and motor fluctuation data obtained from patient diaries ("on" without dyskinesia, "on" with dyskinesia, and "off"). Seven of 10 subjects provided data that could be evaluated. There were two administrative dropouts, and one individual was eliminated from the study because of recrudescence of hallucinations. The median daily L-Dopa dose decreased from 1,400 to 400 mg (p = 0.018, Wilcoxon test). Unified Parkinson's Disease Rating Scale motor scores were unchanged. Although diary variables improved in most individuals, only the reduction in "off" time attained statistical significance. Adverse effects were mild and consisted mainly of dopaminergic side effects and local skin reactions. The data suggest that Rotigotine CDS is an effective treatment for advanced Parkinson's disease and permits patients to substantially lower L-Dopa doses without loss of antiparkinsonian efficacy. Full-scale controlled clinical trials are warranted. In addition to potential therapeutic benefits, this drug can be used to test the hypothesis that continuous dopaminergic stimulation from the initiation of Parkinson's disease therapy will limit the development of motor complications. Clin Neuropharmacol