Shahnawaz M.,University of Houston |
Tokuda T.,Kyoto Prefectural University of Medicine |
Tokuda T.,Japan Agy For Med R And D Core Research For Evolutionary Medical Science And Technology |
Waraga M.,Higashi Matsudo Municipal Hospital |
And 8 more authors.
JAMA Neurology | Year: 2017
IMPORTANCE Parkinson disease (PD) is a highly prevalent and incurable neurodegenerative disease associated with the accumulation of misfolded α-synuclein (αSyn) aggregates. An important problem in this disease is the lack of a sensitive, specific, and noninvasive biochemical diagnosis to help in clinical evaluation, monitoring of disease progression, and early differential diagnosis from related neurodegenerative diseases. OBJECTIVE To develop a novel assay with high sensitivity and specificity to detect small quantities of αSyn aggregates circulating in cerebrospinal fluid (CSF) of patients affected by PD and related synucleinopathies. DESIGN, SETTING, AND PARTICIPANTS The strategy evaluated in this proof-of-concept study uses the protein misfolding cyclic amplification (PMCA) technology that detects minute amounts of misfolded oligomers by taking advantage of their ability to nucleate further aggregation, enabling a very high amplification of the signal. The technology was first adapted with synthetic αSyn oligomers prepared in vitro and used to screen in 2 blinded cohorts of CSF samples from German and Japanese patients with PD (n = 76) and individuals serving as controls affected by other neurologic disorders (n = 65), neurodegenerative diseases (n = 18), and Alzheimer disease (n = 14). The kinetics of αSyn aggregation were measured by αSyn-PMCA in the presence of CSF samples from the participants to detect αSyn oligomeric seeds present in this biological fluid. The assays were conducted from November 15, 2013, to August 28, 2015. MAIN OUTCOMES AND MEASURES Kinetic parameters correlated with disease severity at the time of sample collection, measured by the Hoehn and Yahr scale, with the lowest grade indicating unilateral involvement with minimal or no functional impairment, and the highest grade defining patients with complete confinement to wheelchair or bed. RESULTS Studies with synthetic αSyn aggregates showed that αSyn-PMCA enabled to detect as little as 0.1 pg/mL of αSyn oligomers. The αSyn-PMCA signal was directly proportional to the amount of αSyn oligomers added to the reaction. A blinded study of CSF samples correctly identified patients affected by PD with an overall sensitivity of 88.5%(95%CI, 79.2%-94.6%) and specificity of 96.9% (95%CI, 89.3%-99.6%). The αSyn-PMCA results for different patients correlated with the severity of the clinical symptoms of PD (Japanese cohort: Rs=-0.54,P = .006; German cohort: Rs=-0.36, P = .02). CONCLUSIONS AND RELEVANCE The findings suggest that detection of αSyn oligomers by αSyn-PMCA in the CSF of patients affected by PD may offer a good opportunity for a sensitive and specific biochemical diagnosis of the disease. Further studies are needed to investigate the usefulness of αSyn-PMCA to monitor disease progression and for preclinical identification of patients who may develop PD. © 2017 American Medical Association.
The German study on the epidemiology of Parkinsons disease with dementia (GEPAD): More than Parkinson [Die "German study on the epidemiology of Parkinsons disease with dementia" (GEPAD): Mehr als nur Parkinson]
Reichmann H.,Klinik fur Neurologie |
Deuschl G.,University of Kiel |
Riedel O.,TU Dresden |
Spottke A.,University of Bonn |
And 8 more authors.
MMW-Fortschritte der Medizin | Year: 2010
It is unknown, how frequently Parkinson's disease (PD) is complicated by dementia, depression and other neuropsychiatric conditions. An epidemiologic characterisation of the situation in specialised neurologic settings is lacking. The Geman Study on the Epidemiology of Parkinson's Disease with Dementia (GEPAD) is a national representative epidemiological study of n = 1,449 PD patients in n = 315 office-based neurological settings, designed to estimate the prevalence of dementia, depression and other neuropsychiatric conditions in patients with PD of all stages by using standardized clinical assessments. Results: 28.6% met DSM-IV criteria for dementia. 33.6% met criteria for depression and 61% additionally had other clinically significant psychopathological syndromes. Only 29.4% had no neuropsychiatric conditions. GEPAD reveals for the first time comprehensively that the neuropsychiatric burden of PD patients in all stages and even early stages is considerable, posing challenging questions for research and clinical management.
Krenzer M.,University of Marburg |
Oertel W.,University of Marburg |
Trenkwalder C.,Paracelsus Elena Klinik Kassel
Nervenarzt | Year: 2014
Restless legs syndrome (RLS) is the most common neurological sleep disorder affecting 10% of the Caucasian population. The disorder is characterized by painful sensations in the lower limbs, especially during the evening, at night and during rest, resulting in an urge to move the legs and insomnia. As a re sult the quality of life is significantly reduced. Dopaminergic agents, opioids and anticon vulsants have proven to be effective for RLS with only the former being currently licensed; however, affected patients have to be identified, which is not always the case, especially in outpatient settings. Possible impediments to the adequate management of patients with RLS may include a lack of awareness, comorbidities and other medical conditions mimicking RLS. To overcome some of these difficulties practical guidelines for the diagnosis and therapy of RLS are provided. © Springer-Verlag 2014.
Fuhs A.,University of Munster |
Bentama D.,University of Munster |
Antkowiak R.,University of Munster |
Mathis J.,University of Bern |
And 2 more authors.
PLoS ONE | Year: 2014
In a cohort study among 2751 members (71.5% females) of the German and Swiss RLS patient organizations changes in restless legs syndrome (RLS) severity over time was assessed and the impact on quality of life, sleep quality and depressive symptoms was analysed. A standard set of scales (RLS severity scale IRLS, SF-36, Pittsburgh Sleep Quality Index and the Centre for Epidemiologic Studies Depression Scale) in mailed questionnaires was repeatedly used to assess RLS severity and health status over time and a 7-day diary once to assess short-term variations. A clinically relevant change of the RLS severity was defined by a change of at least 5 points on the IRLS scale. During 36 months follow-up minimal improvement of RLS severity between assessments was observed. Men consistently reported higher severity scores. RLS severity increased with age reaching a plateau in the age group 45-54 years. During 3 years 60.2% of the participants had no relevant (65 points) change in RLS severity. RLS worsening was significantly related to an increase in depressive symptoms and a decrease in sleep quality and quality of life. The short-term variation showed distinctive circadian patterns with rhythm magnitudes strongly related to RLS severity. The majority of participants had a stable course of severe RLS over three years. An increase in RLS severity was accompanied by a small to moderate negative, a decrease by a small positive influence on quality of life, depressive symptoms and sleep quality.©2014 Fuhs et al.
PubMed | Paracelsus Elena Klinik Kassel and Vanderbilt University
Type: Journal Article | Journal: Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine | Year: 2015
To clarify whether motor behaviors and/ or vocalizations during REM sleep, which do not yet fulfill diagnostic criteria for REM sleep behavior disorder (RBD) and were defined as REM sleep behavioral events (RBEs), correspond to dream enactments.13 subjects (10 patients with Parkinson disease [PD] and 3 healthy controls) originally identified with RBE in a prospective study (DeNoPa cohort) were reinvestigated 2 years later with 2 nights of video-supported polysomnography (vPSG). The first night was used for sleep parameter analysis. During the 2nd night, subjects were awakened and questioned for dream recall and dream content when purposeful motor behaviors and/or vocalizations became evident during REM sleep. REM sleep without atonia (RWA) was analyzed on chin EMG and the cutoff set at 18.2% as specific for RBD.At the time of this investigation 9 of 13 subjects with previous RBE were identified with RBD based upon clinical and EMG criteria. All recalled vivid dreams, and 7 subjects were able to describe dream content in detail. Four of 13 subjects with RBE showed RWA values below cutoff values for RBD. Three of these 4 subjects recalled having non-threatening dreams, and 2 (of these 3) were able to describe these dreams in detail.RBE with RWA below the RBD defining criteria correlate to dreaming in this selected cohort. There is evidence that RBEs are a precursor to RBD.
Doppler K.,University of Würzburg |
Ebert S.,University of Würzburg |
Uceyler N.,University of Würzburg |
Trenkwalder C.,Paracelsus Elena Klinik Kassel |
And 3 more authors.
Acta Neuropathologica | Year: 2014
The deposition of alpha-synuclein in the brain, the neuropathological hallmark of Parkinson's disease (PD), follows a distinct anatomical and temporal sequence. This study aimed to characterize alpha-synuclein deposition in cutaneous nerves from patients with PD. We further strived to explore whether peripheral nerve involvement is intrinsic to PD and reflective of known features of brain pathology, which could render it a useful tool for pathogenetic studies and pre-mortem histological diagnosis of PD. We obtained skin biopsies from the distal and proximal leg, back and finger of 31 PD patients and 35 controls and quantified the colocalization of phosphorylated alpha-synuclein in somatosensory and autonomic nerve fibers and the pattern of loss of different subtypes of dermal fibers. Deposits of phosphorylated alpha-synuclein were identified in 16/31 PD patients but in 0/35 controls (p < 0.0001). Quantification of nerve fibers revealed two types of peripheral neurodegeneration in PD: (1) a length-dependent reduction of intraepidermal small nerve fibers (p < 0.05) and (2) a severe non-length-dependent reduction of substance P-immunoreactive intraepidermal nerve fibers (p < 0.0001). The latter coincided with a more pronounced proximal manifestation of alpha-synuclein pathology in the skin. The histological changes did not correlate with markers of levodopa toxicity such as vitamin B12 deficiency. Our findings suggest that loss of peripheral nerve fibers is an intrinsic feature of PD and that peripheral nerve changes may reflect the two types of central alpha-synuclein-related PD pathology, namely neuronal death and axonal degeneration. Detection of phosphorylated alpha-synuclein in dermal nerve fibers might be a useful diagnostic test for PD with high specificity but low sensitivity. © 2014 The Author(s).