Biomedical subjects

Pierre R Burkhard

Publications and source records attributed to Pierre R Burkhard.

At least 19 recordsLinked to original sources

PubMed2006

Long-duration response to levodopa in patients with advanced Parkinson disease treated with subthalamic deep brain stimulation.

BACKGROUND: Long-duration response (LDR) to levodopa is supposed to decrease with Parkinson disease (PD) progression, but direct observation of this response in advanced PD has never been performed. OBJECTIVE: To study the LDR to levodopa in patients with advanced PD treated with subthalamic deep brain stimulation (DBS). DESIGN AND SETTING: We studied 30 consecutive patients with PD who underwent subthalamic DBS. One group had no antiparkinsonian treatment since surgery (no-levodopa group), whereas medical treatment had to be reinitiated in the other group (levodopa group). MAIN OUTCOME MEASURE: Motor subscale score of the Unified Parkinson's Disease Rating Scale. RESULTS: Compared with preoperative assessment, evaluation 6 months postoperatively with DBS turned off for 3 hours found a worsening of the motor subscale score of the Unified Parkinson's Disease Rating Scale in the no-levodopa group. This worsening being absent in the levodopa group, it probably reflected the loss of the LDR to levodopa in the no-levodopa group. When DBS was turned on, postoperative motor subscale scores of the Unifid Parkinson's Disease Rating Scale in both groups were similar to preoperative scores while receiving medication, suggesting that subthalamic DBS compensated for the short-duration response and LDR to levodopa. CONCLUSIONS: Our results suggest that the LDR to levodopa remains significant even in advanced PD, and that subthalamic DBS compensates for the short-duration response and LDR to levodopa.

Aged↗

PubMed2006

Does subthalamic nucleus deep brain stimulation really improve quality of life in Parkinson's disease?

We investigated the impact of subthalamic nucleus (STN) deep brain stimulation (DBS) on quality of life (QOL) in patients with advanced Parkinson's disease, as self-assessed before and after surgery by completing the Parkinson's Disease Questionnaire (PDQ39). In addition to this prospective evaluation, we asked patients postoperatively to evaluate their preoperative QOL. In the prospective assessment, results showed that patients perceived a general improvement of QOL after the STN DBS. However, when evaluated retrospectively, they tended to overestimate their preoperative functioning, therefore obscuring the improvement found prospectively. This observation highlights the impact of the method used on obtained results when assessing the effects of STN DBS.

Activities of Daily Living↗

PubMed2006

Fulminant Lewy body disease.

The clinical distinction between Parkinson's disease (PD) with dementia (PDD) and dementia with Lewy bodies (DLB) is challenged by most neuropathological studies showing nearly identical changes in both conditions. We report an unusual case of PD evolving into a rapidly progressive dementia leading to death within 3 months that showed nearly all clinical features of DLB. At autopsy, numerous Lewy bodies and Lewy neurites were found in several areas of the brainstem, the limbic system, and the neocortex, consistent with pure DLB. This case demonstrates that Lewy body disease may exhibit a dramatic course without any coexisting pathology and exemplifies that PD, PDD, and DLB may sometimes represent sequential, yet overlapping, phenotypes of a same clinicopathological entity.

14-3-3 Proteins↗

PubMed2006

Age-related proteome analysis of the mouse brain: a 2-DE study.

2-DE remains the most popular and versatile protein separation method among a rapidly growing array of various proteomics technologies. However, variability in sample processing, experimental design and data analyses results in a limited cross-validation between studies performed in different laboratories. One of the goals of the Human Proteome Organization (HUPO) is to establish standards and guidelines for proteomics studies. We contributed to the HUPO Brain Proteome Project by analyzing brains from neonatal and adult mice using 2-DE. Here we propose a standard workflow to analyze 2-DE images and extract statistically significant differences. After differential analysis and identification by MALDI-TOF/TOF, dihydropyrimidinase-related proteins, brain FABP, stathmin, isocitrate dehydrogenase, gamma enolase, annexin V, glutamine synthetase, creatine kinase B chain, triosephosphate dehydrogenase, and malate dehydrogenase were found differentially expressed between the two groups. The functions and potential mechanisms underlying the variation observed for these proteins are discussed.

Aging↗

PubMed2006

Identification of brain cell death associated proteins in human post-mortem cerebrospinal fluid.

Following any form of brain insult, proteins are released from damaged tissues into the cerebrospinal fluid (CSF). This body fluid is therefore an ideal sample to use in the search for biomarkers of neurodegenerative disorders and brain damage. In this study, we used human post-mortem CSF as a model of massive brain injury and cell death for the identification of such protein markers. Pooled post-mortem CSF samples were analyzed using a protocol that combined immunoaffinity depletion of abundant CSF proteins, off-gel electrophoresis, SDS-PAGE and protein identification by LC-MS/MS. A total of 299 proteins were identified, of which 172 proteins were not previously described to be present in CSF. Of these 172 proteins, more than 75% have been described as intracellular proteins suggesting that they were released from damaged cells. Immunoblots of a number of proteins were performed on individual post-mortem CSF samples and confirmed elevated concentrations in post-mortem CSF compared to ante-mortem CSF. Interestingly, among the proteins specifically identified in the post-mortem CSF, several have been previously described as biochemical markers of brain damage.

Biomarkers↗

PubMed2005

PARK7 and nucleoside diphosphate kinase A as plasma markers for the early diagnosis of stroke.

BACKGROUND: Plasma markers for stroke could be useful in diagnosis and prognosis and in prediction of response of stroke patients to therapy. PARK7 and nucleoside diphosphate kinase A (NDKA) are increased in human postmortem cerebrospinal fluid (CSF), a model of global brain insult, suggesting that measurement in CSF and, more importantly, in plasma may be useful as a biomarker of stroke. METHODS: We used ELISA to measure PARK7 and NDKA in plasma in 3 independent European and North American retrospective studies encompassing a total of 622 stroke patients and 165 control individuals. RESULTS: Increases in both biomarkers were highly significant, with sensitivities of 54%-91% for PARK7 and 70%-90% for NDKA and specificities of 80%-97% for PARK7 and 90%-97% for NDKA. The concentrations of both biomarkers increased within 3 h of stroke onset. CONCLUSIONS: PARK7 and NDKA may be useful plasma biomarkers for the early diagnosis of stroke. In addition, this study demonstrated the utility of analysis of postmortem CSF proteins as a first step in the discovery of plasma markers of ischemic brain injury.

Biomarkers↗

PubMed2005

Prostaglandin D2 synthase and its post-translational modifications in neurological disorders.

Prostaglandin D2 synthase (PGDS) (beta-trace protein) is a highly abundant cerebrospinal fluid (CSF) glycoprotein. A number of studies have been performed to determine the potential value of this protein for the diagnosis of various neurological disorders. The measurement of total PGDS levels in CSF has proved marginally useful for this purpose, but promising results were obtained while investigating changes in the posttranslational modifications (PTM) pattern. Using 2-DE analysis, we previously showed that PGDS is differentially expressed in ante- and post mortem CSF samples. In the present study, we examined whether the PGDS isoforms may help to distinguish stroke and neurodegenerative disease patients from healthy subjects. The pattern of PGDS PTM was analyzed in CSF from patients with various neurological disorders (n = 44) using IEF/immunoblotting techniques. Strong alterations of this pattern were detected in patients with different forms of degenerative dementia. These findings are consistent with PGDS being altered in some neurological diseases and provide new opportunities for clinical applications.

Aged↗

PubMed2005

Truncated cystatin C in cerebrospiral fluid: Technical [corrected] artefact or biological process?

Cystatin C, a low molecular weight cysteine proteinase inhibitor present in human body fluids at physiological concentrations, is more expressed in cerebrospinal fluid (CSF) than in plasma. Mass spectrometric characterization showed that after 3 months of storage of human CSF at -20 degrees C, cystatin C was cleaved in the peptide bond between R8 and L9 and lost its eight N-termini amino acids, whereas this cleavage did not occur when stored at -80 degrees C. This truncation occurred in all CSF samples studied irrespective of the underlying neurological status, indicating a storage-related artefact rather than a physiological or pathological processing of the protein. These results stress the importance of optimal preanalytical storage conditions of any sample prior to proteomics studies.

Artifacts↗

PubMed2004

Skull base cerebrospinal fluid fistula: a novel detection method based on two-dimensional electrophoresis.

BACKGROUND: The detection of the presence of cerebrospinal fluid (CSF) in nasal secretions contaminated with blood and mucus remains a challenging clinical problem. METHODS: A prospective study was conducted from November 1998 to February 2002, including 42 patients. Samples (250 microL) of nasal secretions were analyzed by two-dimensional electrophoresis (2-DE). Plasma, mucus, and CSF were identified by specific proteins markers corresponding to characteristic trains of spots. Intrathecal injection of fluorescein followed by the detection of fluorescein on endoscopic examination of the nasal cavities was considered a positive reference for CSF rhinorrhea. RESULTS: In all cases of positive fluorescein test, we unambiguously observed the presence of several specific CSF markers onto the 2-DE gels. Conversely, all negative fluorescein tests were associated with the absence of CSF-specific spots. CONCLUSIONS: Two-DE analyses of biologic fluids of nasal origin should be considered as a reliable diagnostic tool in case of suspicion of CSF leak.

Adolescent↗

PubMed2004

Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists.

We report on 4 new cases of valvular heart disease in Parkinson's disease patients treated with the ergot derivative dopamine agonists pergolide and cabergoline. Noninflammatory fibrotic degeneration of cardiac valves has been reported to occur in patients with carcinoid syndrome and to occasionally complicate therapies with the anti-migraine ergot alkaloid ergotamine and methysergide and with the appetite suppressants fenfluramine and dexfenfluramine. In these cases, the pathogenesis is suspected to involve serotonin-mediated abnormal fibrogenesis by means of the 5-HT2B receptors, which are expressed in the fibroblasts of heart valves. Based on strikingly similar echocardiographic and histopathological features, we strongly suspect that ergot-derived dopamine agonists may cause a valvular heart disease nearly identical to that seen in those conditions. These cases add to a rapidly growing and worrying list of similar published reports, suggesting that we may well be facing a novel, yet unrecognized, complication of this class of agents, which are widely used not only in Parkinson's disease but also in restless legs syndrome and various common endocrine dysfunctions. Therefore, until more is known about the true prevalence of this side effect, we propose that an assessment of cardiac function be performed before and in the course of a long-term therapy with ergot derivative dopamine agonists.

Adult↗

PubMed2004

Cystatin C as a potential cerebrospinal fluid marker for the diagnosis of Creutzfeldt-Jakob disease.

The definite diagnosis of Creutzfeldt-Jakob disease (CJD), the most common form of human prion diseases, relies upon neuropathological data usually obtained at autopsy. In living patients, the diagnosis, based on suggestive clinical features and EEG abnormalities, can be aided by the detection of altered levels of isoforms of the 14-3-3 protein in the cerebrospinal fluid (CSF). However, the validity of this test has been recently challenged and the search for other, more reliable biomarkers for CJD remains highly desirable. The present study describes the identification of a new potential surrogate marker in the CSF of CJD-affected patients. A preliminary study employing surface-enhanced laser desorption/ionization-time of flight (SELDI-TOF) technology highlighted a protein at 13.4 kDa in a small group (n = 8) of CJD-affected patients. Further analysis aimed at identifying this protein using cationic exchange chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed it to be cystatin C. Additional immunoblot assays confirmed that the level of cystatin C was significantly increased (p </= 0.05) in all tested samples (n = 8). We conclude that the analysis of cystatin C levels in CSF could be useful as a pre-mortem indicator of the disease.

Biomarkers↗

PubMed2004

ApoC-I and ApoC-III as potential plasmatic markers to distinguish between ischemic and hemorrhagic stroke.

Early diagnosis and immediate therapeutic interventions are crucial factors to reduce the damage extent and the risk of death. Currently, the diagnosis of stroke relies on neurological assessment of the patient and neuro-imaging techniques including computed tomography and/or magnetic resonance imaging scan. An early diagnostic marker of stroke, ideally capable to discriminate ischemic from hemorrhagic stroke would considerably improve patient acute management. Using surface-enhanced laser desorption/ionization (SELDI) technology, we aimed at finding new early diagnostic plasmatic markers of stroke. Strong anionic exchange (SAX) SELDI profiles of plasma samples from 21 stroke patients were compared to 21 samples from healthy controls. Seven peaks appeared to be differentially expressed with significant p values (p < 0.05). Proteins were stripped from the SAX chips, separated on a one-dimensional electrophoresis (1-DE) gel and stained using mass spectrometry (MS)-compatible silver staining. Following in-gel tryptic digestion, the peptides were analyzed by MS. Four candidate proteins were identified as apolipoprotein CI (ApoC-I), apolipoprotein CIII (ApoC-III), serum amyloid A (SAA), and antithrombin-III fragment (AT-III fragment). Assessment of ApoC-I and ApoC-III levels in plasma samples using a sandwich enzyme-linked immunosorbent assay (ELISA) allowed to distinguish between hemorrhagic (n = 15) and ischemic (n = 16) stroke (p < 0.001). To the best of our knowledge, ApoC-I and ApoC-III are the first reported plasmatic biomarkers capable to accurately distinguish between ischemic and hemorrhagic stroke in a small number of patients. It requires further investigation in a large cohort of patients.

Adult↗

PubMed2004

Identification of post-mortem cerebrospinal fluid proteins as potential biomarkers of ischemia and neurodegeneration.

Only few biological markers are currently available for the routine diagnosis of brain damage-related disorders including cerebrovascular, dementia, and other neurodegenerative diseases. In this study, post-mortem cerebrospinal fluid samples were used as a model of massive brain insult to identify new markers potentially relevant for neurodegeneration. The protein pattern of this sample was compared to the one of cerebrospinal fluid from healthy subjects by two-dimensional gel electrophoresis. Using gel imaging, N-terminal microsequencing, mass spectrometry, and immunodetection techniques, we identified 13 differentially expressed proteins. Most of these proteins have been previously reported to be somehow associated with brain destruction or with the molecular mechanisms underlying certain neurodegenerative conditions. These data indicate that the identified proteins indeed represent potential biomarkers of brain damage. We recently showed that H-FABP, a protein highly homologous to E-FABP and A-FABP identified in this study, is a potential marker of Creutzfeldt-Jakob disease and stroke.

Autopsy↗

PubMed2004

Gait assessment in Parkinson's disease: toward an ambulatory system for long-term monitoring.

An ambulatory gait analysis method using body-attached gyroscopes to estimate spatio-temporal parameters of gait has been proposed and validated against a reference system for normal and pathologic gait. Later, ten Parkinson's disease (PD) patients with subthalamic nucleus deep brain stimulation (STN-DBS) implantation participated in gait measurements using our device. They walked one to three times on a 20-m walkway. Patients did the test twice: once STN-DBS was ON and once 180 min after turning it OFF. A group of ten age-matched normal subjects were also measured as controls. For each gait cycle, spatio-temporal parameters such as stride length (SL), stride velocity (SV), stance (ST), double support (DS), and gait cycle time (GC) were calculated. We found that PD patients had significantly different gait parameters comparing to controls. They had 52% less SV, 60% less SL, and 40% longer GC. Also they had significantly longer ST and DS (11% and 59% more, respectively) than controls. STN-DBS significantly improved gait parameters. During the stim ON period, PD patients had 31% faster SV, 26% longer SL, 6% shorter ST, and 26% shorter DS. GC, however, was not significantly different. Some of the gait parameters had high correlation with Unified Parkinson's Disease Rating Scale (UPDRS) subscores including SL with a significant correlation (r = -0.90) with UPDRS gait subscore. We concluded that our method provides a simple yet effective way of ambulatory gait analysis in PD patients with results confirming those obtained from much more complex and expensive methods used in gait labs.

Acceleration↗

PubMed2004

Cerebrospinal fluid tau and Abeta42 concentrations in healthy subjects: delineation of reference intervals and their limitations.

Many limitations and conflicting results have cast serious doubts on the validity of cerebrospinal fluid tau and Abeta42 levels for the biological diagnosis of Alzheimer's disease, particularly extreme variations of the reference limits found by unrelated groups as a consequence of different reference populations used. In this study, we addressed the issue of defining reference limits for cerebrospinal fluid tau and Abeta42 in healthy adult individuals. One hundred and five neurologically intact subjects were enrolled according to strict inclusion criteria, 10 of them with autopsy confirmation of brain integrity. All cerebrospinal fluid samples were similarly and optimally processed as were the dosage methods used and the statistical analyses performed. A robust correlation with age was demonstrated for Abeta42 but not for tau. For tau, we found that an upper cut-off value of 443 ng/l allowed 95% of the subjects to be correctly classified as normal. For Abeta42, a lower cut-off value of 90 ng/l allowed a correct classification of 90% of the subjects. However, a large variance of the reference values, partly explained by the potential contamination of the reference population with presymptomatic dementia patients, may limit the use of reference limits based on living subjects. We propose that the issue of defining reference limits for both cerebrospinal fluid tau and Abeta42 may ultimately be settled by studying large numbers of autopsy-proven neurologically intact individuals only.

Adult↗

PubMed2003

Fatty acid binding protein as a serum marker for the early diagnosis of stroke: a pilot study.

No biological marker is currently available for the routine diagnosis of stroke. The aim of this pilot study was to determine whether heart-fatty acid binding protein (H-FABP) could be used as a valid diagnostic biomarker for stroke, as compared with neuron-specific enolase (NSE) and S100B proteins. Using two-dimensional gel electrophoresis separation of cerebrospinal fluid proteins and mass spectrometry techniques, FABP was found elevated in the cerebrospinal fluid of deceased patients, used as a model of massive brain damage. Because H-FABP, a FABP form present in many organs, is also localized in the brain, an enzyme-linked immunosorbant assay was developed to detect H-FABP in stroke versus control plasma samples. However, H-FABP being also a marker of acute myocardial infarction (AMI), troponin-I and creatine kinase-MB levels were assayed at the same time in order to exclude any concomitant heart damage. NSE and S100B levels were assayed simultaneously. These assays were assessed in serial plasma samples from 22 control patients with no AMI or stroke, 20 patients with AMI but no stroke, and 22 patients with an acute stroke but no AMI. Twenty-two out of the 22 control patients and 15 out of the 22 stroke patients were correctly classified, figures much better than those obtained with NSE or S100B, in the same study's population. H-FABP appears to be a valid serum biomarker for the early diagnosis of stroke. Further studies on large cohorts of patients are warranted.

Adult↗

PubMed2003

Chronic parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration.

CONTEXT: The clinical, neuroradiological, and biological characteristics of the so-called acquired hepatocerebral degeneration have not yet been fully determined and its frequency remains largely uncertain. OBJECTIVES: To prospectively study the prevalence of extrapyramidal symptoms in patients with moderate to severe cirrhosis of various causes, to delineate the main neurological features of the condition, and to establish correlations with neuroradiological and biological findings. PATIENTS AND METHODS: During a 1-year period, all consecutive patients with cirrhosis who were potential candidates for liver transplantation were screened for extrapyramidal features. When extrapyramidal features were present, further workup included a detailed neurological examination, magnetic resonance imaging of the brain, a comprehensive battery of neuropsychological tests, extensive blood tests, and, in some cases, cerebrospinal fluid analysis. SETTING: A community-based hospital. RESULTS: From 51 patients screened, 11 (21.6%) exhibited moderate to severe parkinsonism sometimes associated with focal dystonia. Typical features included rapid progression over months, symmetric akinetic-rigid syndrome, postural but not resting tremor, and early postural and gait impairment. Neuropsychiatric manifestations were minimal. Some patients were responsive to levodopa therapy. In all patients, magnetic resonance imaging scans showed striking hyperintensities on T1-weighted images typically involving the substantia nigra and the globus pallidus bilaterally. Whole blood and cerebrospinal fluid manganese concentrations were severalfold above the reference range. CONCLUSIONS: Cirrhosis-related parkinsonism may represent a unique, consistent, and common subset of acquired hepatocerebral degeneration, whose features are permanent and entirely different from acute hepatic encephalopathy episodes. This form of parkinsonism can be clearly distinguished from other forms of parkinsonism of middle to advanced age, based on a suggestive association of clinical, neuroradiological, and biological abnormalities. Our findings support the concept of the toxic effects of manganese being the major determinant of basal ganglia dysfunction leading to the predominantly extrapyramidal central nervous system manifestations of cirrhosis observed in these patients.

Aged↗

PubMed2003

A potential cerebrospinal fluid and plasmatic marker for the diagnosis of Creutzfeldt-Jakob disease.

The recent occurrence of the new variant of Creutzfeldt-Jakob disease (CJD), probably transmitted to humans by cattle affected by the bovine form of spongiform encephalopathy, has generated renewed interest in the clinical issues related to human spongiform encephalopathies. Using the current set of diagnostic tools, these rare but devastating conditions may be difficult to diagnose with accuracy before death. The objective of the present communication is to describe the discovery of a potential cerebrospinal fluid (CSF) and plasmatic marker of human transmissible spongiform encephalopathies. A preliminary two-dimensional electrophoresis approach highlighted a potential neurodegenerative disorder marker called the fatty acid binding protein, FABP. Its heart form, H-FABP, was investigated in a small group of CJD affected patients (n = 8 ) by an immunoassay approach. The amount of FABP appeared to be significantly (p< or = 0.05) increased in all tested samples. H-FABP detection could therefore be helpful as a blood screening test for a pre-mortem diagnosis of the disease and also to prevent the risk of iatrogenic transmission of CJD through blood transfusion.

Creutzfeldt-Jakob Syndrome↗