Characterizing mild cognitive impairment in incident Parkinson disease: the ICICLE-PD study.

OBJECTIVE: To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers. METHODS: Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria. RESULTS: The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal ß-amyloid 1-42 levels (ß standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower ß-amyloid 1-42 and 1-40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold. CONCLUSIONS: In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal ß-amyloid 1-42 and 1-40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.

Cerebrospinal fluid biomarkers in Parkinson disease.

Clinical diagnosis of Parkinson disease (PD) is difficult in early stages of disease, with high risk of misdiagnosis. The long preclinical phase of PD provides the possibility for early therapeutic intervention once disease-modifying therapies have been developed, but lack of biomarkers for early diagnosis and monitoring of disease progression represents a major obstacle to achievement of this goal. Accordingly, research efforts aimed at identification of novel biomarkers have been increasing in the past 5 years. Cerebrospinal fluid (CSF) is an accessible source of brain-derived proteins, which mirror molecular changes that take place in the CNS. In this Review, we discuss evidence from numerous studies that have focused on identification of candidate CSF biomarkers for PD. Notably, molecular pathways related to α-synuclein, tau and ß-amyloid peptides have received considerable attention. CSF levels of the protein DJ-1 are also of interest, although further investigation of this candidate marker is required. These studies support the usefulness of a combination of various CSF biomarkers of PD to increase diagnostic accuracy during early phases of the disease, and to differentiate PD from other neurodegenerative disorders.

Cerebrospinal fluid α-synuclein levels are elevated in multiple sclerosis and neuromyelitis optica patients during replase.

The concept that the immune system plays a central role in the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica (NMO) was indisputable. However, neurodegenerative pathological features including loss of axons and neurons were also found in the lesions of these diseases. α-Synuclein is one of the most abundant proteins in pre-synaptic terminals. Recently, many research show α-synuclein level in CSF may reflect the progression of synaptic dysfunction and neuronal apoptosis. Whether the levels of CSF α-synuclein are changed in MS and NMO patients remain unknown. In this study, CSF α-synuclein was measured by an enzyme-linked immunosorbent assay (ELISA) in MS (n = 18) patients, NMO (n = 22) patients, Parkinson's disease patients (n = 9), and the controls (n = 11). We found concentration of α-synuclein in MS and NMO patients were significantly higher than Parkinson's disease subgroup and the controls. Both MS and NMO revealed an increased disease disability with increased CSF α-synuclein. Thus, CSF α-synuclein may be reflect injure axons and neurons in inflammatory demyelinating diseases.

Multilevel somatosensory evoked potentials and cerebrospinal proteins: indicators of spinal cord injury in thoracoabdominal aortic aneurysm surgery.

OBJECTIVE: Multilevel somatosensory evoked potentials (SSEP) and the release of biochemical markers in cerebrospinal fluid (CSF) were investigated to identify patients with spinal cord ischemia during thoracoabdominal aortic repair and/or a vulnerable spinal cord during the postoperative period. METHODS: Thirty-nine consecutive patients undergoing elective aneurysm repair using distal aortic perfusion and cerebrospinal fluid drainage were studied. Continuous SSEP were monitored using nerve stimulation of the right and left posterior tibial nerves with signal recording at the level of both common peroneal nerves, the cervical cord and at the cortical level. CSF concentrations of the markers glial fibrillary acidic protein (GFAp), the light subunit of neurofilament triplet protein (NFL), and S100B were determined at different time points from before surgery until 3 days postoperatively. RESULTS: SSEP indicated spinal cord ischemia in two patients leading to additional intercostal artery reattachments. In one of them the signal loss was permanent and the patient woke up with paraplegia. In the other the signal returned but the patient later developed delayed paraplegia. Three patients without SSEP indications of spinal cord ischemia during surgery later developed delayed paraplegia. The patients with spinal cord symptoms had significant increases, during the postoperative period of CSF biomarkers GFAp (571-fold), NFL (14-fold) and S100B (18-fold) compared to asymptomatic patients. GFAp increased before or in parallel to onset of symptoms in the patients with delayed paraplegia. CONCLUSIONS: Peroperative multilevel SSEP has a high specificity in detecting spinal cord ischemia but does not identify all patients with a postoperative vulnerable spinal cord. Biochemical markers in CSF increase too late for intraoperative monitoring but GFAp is promising for identifying patients at risk for postoperative delayed paraplegia.

Neural progenitors populate the cerebrospinal fluid of preterm patients with hydrocephalus.

OBJECTIVES: To evaluate cerebrospinal fluid (CSF) of preterm patients with hydrocephalus for neural progenitors. STUDY DESIGN: This report describes a prospective study of CSF obtained from preterm infants, either with progressive posthemorrhagic hydrocephalus (PPHH) or without known intercranial pathology. Cells recovered by centrifugation were analyzed by reverse transcriptase-polymerase chain reaction or by immunocytometry. Alternatively, cells were cultured by using methods permissive to neural progenitor growth and analyzed by immunocytochemistry and Western blotting. RESULTS: Human CSF cells were obtained from 20 preterm infants at approximately 27 weeks estimated gestational age (15 infants with PPHH, 5 control infants). The number of these cells removed over time from patients with PPHH were substantial, based on our calculations. Cells recovered from patients with PPHH transcribe markers for neural progenitors, all the mature cells types of the central nervous system, and a large battery of chondroitin sulfate proteoglycan genes, including the entire aggrecan/lectican family. These cells proliferated in culture, and precursor markers were detected by Western blotting, immunocytochemistry, and cytometry. Cells could not be cultured from control patients. CONCLUSIONS: Neural progenitor accumulation in CSF could confound the clinical interpretation of CSF cell counts in hydrocephalus and may play as yet undetermined roles in the biology of injury after hydrocephalus. These findings suggest the potential for neural stem cell propagation from CSF.

Cerebrospinal fluid of newborn infants contains a deglycosylated form of the intermediate filament nestin.

Nestin is an intermediate filament protein found in CNS progenitor cells. Nestin reappears in CNS tumor cells and reactive astrocytes after CNS injury. In this study we investigated whether nestin could be detected in the cerebrospinal fluid (CSF) of newborn infants and whether expression levels change with gestational age (GA) and/or brain injury. Using Western blot analysis, we examined the expression of nestin in the CSF of newborn infants (GA 25-42 wk) with asphyxia (n = 14), periventricular leukomalacia and peri(intra)ventricular hemorrhage (n = 7), and in a control group (n = 11). Protein extract from the periventricular brain tissue of a 1-wk-old infant was also analyzed. Nestin was detected in all the CSF samples and in the protein extract from the periventricular brain tissue. Although the CSF levels of nestin expression did not change with increasing GA, the asphyxia group had significantly lower levels of nestin in the CSF. An unexpected finding was that brain-derived nestin had an apparent molecular mass of approximately 240 kD, whereas all analyzed CSF samples contained two nestin-immunoreactive proteins at 200 and 220 kD. Experimental deglycosylation of the 240-kD form reduced the molecular mass to 220 kD, indicating that nestin undergoes a specific deglycosylation upon release into the CSF.

Blood and cerebrospinal fluid anomalies in brain ageing and Alzheimer's disease.

The glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), S100 protein (S100), gamma gamma-enolase and neurofilament proteins were determined in the CSF of neurological patients. In Alzheimer's disease (AD), the GFAP values were very often increased but this was not specific to this disease. In 2 cases of familial AD, increases in neurofilament protein were detected. The determination of autoantibodies against neurofilament proteins in blood showed rather low values in AD, although they were higher than in subacute sclerosing panencephalitis (SSPE) and Chagas' disease. Increases were observed in diseases not related to AD such as vascular disorders and Parkinson's disease.

Devic's syndrome: antibody to glial fibrillary acidic protein in cerebrospinal fluid.

The cerebrospinal fluid of a patient with Devic's syndrome contained antiglial fibrillary acidic protein antibody. The serum level of antibody was less than that in cerebrospinal fluid, and the antibody was probably synthesized within the central nervous system. Similar antibody was not found in another patient with Devic's syndrome or in patients with multiple sclerosis. The role of the antibody in the patient's illness is uncertain, but is one of the few instances in which antibody against a specific brain antigen has been described in human demyelinating disease.