Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - A consensus report.

BACKGROUND: Vascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) is emerging as a major homogeneous subtype. Its progressive course raises the need for biomarker identification and/or development for adequate therapeutic interventions to be tested. In order to shed light in the current status on biochemical markers for VCI-SSVD, experts in field reviewed the recent evidence and literature data. METHOD: The group conducted a comprehensive search on Medline, PubMed and Embase databases for studies published until 15.01.2017. The proposal on current status of biochemical markers in VCI-SSVD was reviewed by all co-authors and the draft was repeatedly circulated and discussed before it was finalized. RESULTS: This review identifies a large number of biochemical markers derived from CSF and blood. There is a considerable overlap of VCI-SSVD clinical symptoms with those of Alzheimer's disease (AD). Although most of the published studies are small and their findings remain to be replicated in larger cohorts, several biomarkers have shown promise in separating VCI-SSVD from AD. These promising biomarkers are closely linked to underlying SSVD pathophysiology, namely disruption of blood-CSF and blood-brain barriers (BCB-BBB) and breakdown of white matter myelinated fibres and extracellular matrix, as well as blood and brain inflammation. The leading biomarker candidates are: elevated CSF/blood albumin ratio, which reflects BCB/BBB disruption; altered CSF matrix metalloproteinases, reflecting extracellular matrix breakdown; CSF neurofilment as a marker of axonal damage, and possibly blood inflammatory cytokines and adhesion molecules. The suggested SSVD biomarker deviations contrasts the characteristic CSF profile in AD, i.e. depletion of amyloid beta peptide and increased phosphorylated and total tau. CONCLUSIONS: Combining SSVD and AD biomarkers may provide a powerful tool to identify with greater precision appropriate patients for clinical trials of more homogeneous dementia populations. Thereby, biomarkers might promote therapeutic progress not only in VCI-SSVD, but also in AD.

CSF biomarker profile and diagnostic value in vascular dementia.

BACKGROUND AND PURPOSE: The differential diagnosis between vascular dementia (VD) and Alzheimer's disease (AD) or mixed dementia (MD) is not always easy in clinical practice. The purpose of the present study was to evaluate the cerebrospinal fluid (CSF) biomarkers tau protein in its total (tau(T)) or hyperphosphorylated at threonin-181(tau(P-181)) form and beta amyloid peptide 1-42 (A beta 42) alone and their combinations to investigate their diagnostic value in the discrimination between VD and AD or MD. METHODS: The above CSF biomarkers were determined in duplicate and blind to the clinical diagnosis by double sandwich, enzyme-linked immunosorbent assay (ELISA) commercial kits (Innogenetics, Gent, Belgium) in 92 AD patients, 23 VD patients, 17 patients with MD and 68 controls. RESULTS: Alzheimer's disease and MD showed increased levels of tau(T), tau(P) and reduced levels of A beta 42 as compared with the controls. The best discrimination between VD and AD or MD was achieved by the combination of all three biomarkers, correctly classifying >or=85% of patients, either in the form of a discriminant function or in the form of the tau(T) x tau(P-181)/A beta 42 formula. CONCLUSIONS: Cerebrospinal fluid biomarkers may be a useful adjunct for the discrimination between AD/ MD and VD in every day clinical practice.

Circulating interleukin-10 and interleukin-12 in Parkinson's disease.

BACKGROUND: Interleukin (IL)-12 is a heterodimeric cytokine produced by activated blood monocytes, macrophages and glial cells. It enhances differentiation and proliferation of T cells and increases production of proinflammatory cytokines. IL-10 is a pleiotropic cytokine produced by both lymphocytes and mononuclear phagocytes including microglia. Recent studies demonstrated the neuroprotective effect of IL-10. There is little information about the involvement of IL-12 or IL-10 in the pathophysiology of Parkinson's disease (PD). OBJECTIVES: The objective of our study was to assess the role of IL-12 as a potential marker of immune reactions in patients with PD and to investigate whether IL-10, an immunosuppressive cytokine, may have a neuroprotective effect in the pathogenesis of PD. PATIENTS AND METHODS: We measured using immunoassay serum IL-12 and IL-10 levels in 41 patients with PD in comparison with serum levels in 19 healthy subjects (controls) age and sex matched. IL-12 and IL-10 levels were tested for correlation with sex, age, disease duration, Hoehn and Yahr stage and the UPDRS III score. RESULTS: The PD group presented with significantly increased IL-10 levels when compared with the control group (P = 0.02). The increase observed was not affected by the treatment status. A strong and significant correlation between IL-10 and IL-12 levels was observed in patients with PD (R(S) = 0.7, P < 0.000001). CONCLUSIONS: Our findings suggest that IL-10 may be involved in the pathogenetic mechanisms of PD. The elevation of IL-10 and the significant correlation between IL-10 and IL-12, a proinflammatory cytokine, may suggest that immunological disturbances and neuroprotective mechanisms are involved in patients with PD.

A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer's disease.

BACKGROUND: Different cerebrospinal fluid (CSF) amyloid-beta 1-42 (Abeta(1-42)), total Tau (Tau) and Tau phosphorylated at threonine 181 (P-Tau) levels are reported, but currently there is a lack of quality control programmes. The aim of this study was to compare the measurements of these CSF biomarkers, between and within centres. METHODS: Three CSF-pool samples were distributed to 13 laboratories in 2004 and the same samples were again distributed to 18 laboratories in 2008. In 2004 six laboratories measured Abeta(1-42), Tau and P-Tau and seven laboratories measured one or two of these marker(s) by enzyme-linked immunosorbent assays (ELISAs). In 2008, 12 laboratories measured all three markers, three laboratories measured one or two marker(s) by ELISAs and three laboratories measured the markers by Luminex. RESULTS: In 2004, the ELISA intercentre coefficients of variance (interCV) were 31%, 21% and 13% for Abeta(1-42), Tau and P-Tau, respectively. These were 37%, 16% and 15%, respectively, in 2008. When we restricted the analysis to the Innotest (N = 13) for Abeta(1-42), lower interCV were calculated (22%). The centres that participated in both years (N = 9) showed interCVs of 21%, 15% and 9% and intra-centre coefficients (intraCV) of variance of 25%,18% and 7% in 2008. CONCLUSIONS: The highest variability was found for Abeta(1-42). The variabilities for Tau and P-Tau were lower in both years. The centres that participated in both years showed a high intraCV comparable to their interCV, indicating that there is not only a high variation between but also within centres. Besides a uniform standardization of (pre)analytical procedures, the same assay should be used to decrease the inter/intracentre variation.

Incidence and clinical presentation of neurosyphilis: a retrospective study of 81 cases.

Aim of the report was the study of the clinical features of neurosyphilis in the last 40 years (1965-2005). The investigation was based on the retrospective review of patients with neurosyphilis hospitalized in our hospital from 1965 to 2005 (period A: 1965-1984 and B: 1985-2005). Eighty one patients with neurosyphilis were studied. Typical forms represent 68.6% of cases of neurosyphilis in period A. In period B, 85.7% of the cases are presented with atypical clinical patterns. Typical forms of the disease were no longer common, while atypical and masked clinical patterns prevailed. Neuropsychiatric symptoms were the most common manifestations of the disease.

MRI Planimetry and Magnetic Resonance Parkinsonism Index in the Differential Diagnosis of Patients with Parkinsonism.

BACKGROUND AND PURPOSE: Differential diagnosis of multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration from Parkinson disease on clinical grounds is often difficult. MR imaging biomarkers could assist in a more accurate diagnosis. We examined the utility of MR imaging surface measurements (MR imaging planimetry) in the differential diagnosis of patients with parkinsonism. MATERIALS AND METHODS: Fifty-two patients with Parkinson-plus (progressive supranuclear palsy, n = 24; corticobasal degeneration, n = 9; multiple system atrophy, n = 19), 18 patients with Parkinson disease, and 15 healthy controls were included. Corpus callosum, midbrain, and pons surfaces; relevant indices; and the Magnetic Resonance Parkinsonism Index were calculated. Corpus callosum subsection analysis was performed, and the corpus callosum posteroanterior gradient was introduced. RESULTS: A Magnetic Resonance Parkinsonism Index value of >12.6 discriminated progressive supranuclear palsy from other causes of parkinsonism with a 91% sensitivity and 95% specificity. No planimetry measurement could accurately discriminate those with multiple system atrophy with parkinsonism from patients with Parkinson disease. A corpus callosum posteroanterior gradient value of ≤191 was highly specific (97%) and moderately sensitive (75%) for the diagnosis of corticobasal degeneration versus all other groups. A midbrain-to-corpus callosum posteroanterior gradient ratio of ≤0.45 was highly indicative of progressive supranuclear palsy over corticobasal degeneration (sensitivity 86%, specificity 88%). CONCLUSIONS: MR imaging planimetry measurements are potent imaging markers of progressive supranuclear palsy and promising markers of corticobasal degeneration but do not seem to assist in the diagnosis of multiple system atrophy with parkinsonism.

Cerebrospinal fluid tau, phospho-tau181 and beta-amyloid1-42 in idiopathic normal pressure hydrocephalus: a discrimination from Alzheimer's disease.

The aim of the present study was the quantitation of total tau protein (tau(T)), tau phosphorylated at threonine 181 (tau(P-181)) and beta-amyloid(1-42) (Abeta42) in the cerebrospinal fluid (CSF) of patients with idiopathic normal pressure hydrocephalus (iNPH), Alzheimer's disease (AD) and controls. Double sandwich ELISAs (Innogenetics) were used for the measurements. Total tau was significantly increased in iNPH and highly increased in AD as compared with the control group, whilst Abeta42 was decreased in both diseases. CSF tau(P-181) levels were significantly increased only in AD, but not in iNPH as compared with the controls. A cut-off level for tau(T) at 300 pg/ml, successfully discriminated AD from normal aging with a 95.8% specificity and 91% sensitivity; whilst the tau(P-181)/tau(T) ratio (cut-off value 0.169) was more specific (100%) but less sensitive (92.5%). For the discrimination of iNPH from AD tau(T) achieved low specificity (77.8%) but high sensitivity (92.5%), whilst tau(P-181) (cut-off value 47.4) was both sensitive and specific (88.7% and 86.7% respectively) for the discrimination of these disorders. The present study, despite being clinical, supports the notion that CSF tau(P-181) alone or in combination with tau(T) may be a useful marker in the discrimination of iNPH from AD.

A novel panel of cerebrospinal fluid biomarkers for the differential diagnosis of Alzheimer's disease versus normal aging and frontotemporal dementia.

BACKGROUND: An early and accurate diagnosis of Alzheimer's disease (AD) is important in order to initiate symptomatic treatment with currently approved drugs and will be of even greater importance with the advent of disease-modifying compounds. METHODS: Protein profiles of human cerebrospinal fluid samples from patients with AD (n = 85), frontotemporal dementia (n = 20), and healthy controls (n = 32) were analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to verify previously discovered biomarkers. RESULTS: We verified 15 protein biomarkers that were able to differentiate between AD and controls, and 7 of these 15 markers also differentiated AD from FTD. CONCLUSION: A panel of cerebrospinal fluid protein markers was verified by a proteomics technology which may potentially improve the accuracy of the AD diagnosis.

IL-15 is elevated in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia.

Interleukin-15 is a novel proinflammatory cytokine. It is produced by activated blood monocytes, macrophages, and glial cells. The objective of our study was to assess the role of interleukin-15 as a marker of increased proinflammatory activity in patients with Alzheimer's disease and frontotemporal dementia. We measured cerebrospinal fluid interleukin-15 levels in 17 patients with Alzheimer's disease and 7 patients with frontotemporal dementia in comparison with 17 patients with amyotrophic lateral sclerosis and 15 patients with Parkinson's disease. Patients with Alzheimer's disease and frontotemporal dementia had significantly higher cerebrospinal fluid interleukin-15 levels compared with patients with noninflammatory neurological diseases (P < .05 and P < .01, respectively). In Alzheimer's disease, a significant positive correlation was noted between interleukin-15 levels and age of onset (R = .48, P = .05). Our findings suggest that interleukin-15 may be implicated in the pathophysiology of Alzheimer's disease and frontotemporal dementia.

The cognitive effects of cholinesterase inhibitor treatment in every-day practice.

OBJECTIVE: Cholinesterase inhibitors (ChEIs) are the treatment of choice in Alzheimer's disease (AD). Their efficacy has been proven in many clinical trials. The aim of the present study was to confirm their cognitive benefit in every day practice as to whether it is similar to that expected from clinical trials. PATIENTS AND METHODS: We reviewed the files of 41 patients suffering from AD or mixed dementia and treated by ChEIs in terms of every day practice. RESULTS: During the first year MMSE scores remained better than or at baseline levels. Following that a gradual decline was noted. However, at any time point, the observed scores were significantly better than the expected ones calculated according to the pre-treatment rate of decline. The post-treatment rate of decline was significantly better than the pre-treatment one, while progression to the next stage of dementia was delayed by 8 months. CONCLUSION: The present observations from every-day practice indicate that there is a small but significant effect of ChEIs in cognition, similar to that observed in clinical trials. Furthermore, a small but significant delay in dementia progression may occur after treatment with ChEIs.

Changes in blood neurotransmitter and steroid levels during evoked vertigo.

HYPOTHESIS AND BACKGROUND: Experimental evidence suggests that steroids as well as various neurotransmitters are critically involved in the functioning of the vestibular system in health and disease. Yet there are no pertinent human data. We hypothesized that changes in the serum levels of cortisol and plasma levels of excitatory and inhibitory neurotransmitters may occur during evoked vertigo. SUBJECTS AND METHODS: Ten healthy volunteers (median age 37, range 21-57) entered the study. Subjects were investigated at rest and at the time of maximal nystagmic reaction during caloric irrigation. The determination of glutamate, aspartate, and gamma-aminobutyric acid (GABA) was performed by reverse phase high-performance liquid chromatography, whereas cortisol measurements were performed with an immunoenzymatic assay with fluorescence polarization. RESULTS: During evoked vertigo, cortisol levels increased from a baseline value of 11.86 (+/-1.272) microg/dl to 14.375 (+/-2.183) microg/dl (p < 0.01), whereas all neurotransmitter levels decreased significantly. Glutamate levels, for instance, fell from a resting value of 25.99 (+/-6.30) ng/ml to 17.40 (+/-5.50) ng/ml (p < 0.001), and aspartate and GABA decreased as well. CONCLUSION: Evoked vertigo is consistently associated with an increase in steroid serum levels and accompanying decreases in the plasma levels of glutamate, aspartate, and GABA. The possible underlying mechanisms and the functional significance of these findings are discussed.

Gadopentetate dimeglumine-enhanced MR in the diagnosis of the Tolosa-Hunt syndrome.

A 54-year-old man first was admitted with a right oculomotor nerve palsy that ameliorated spontaneously. Two months later, he was readmitted with right proptosis, ophthalmoplegia, and optic nerve involvement. MR showed an enlarged right cavernous sinus. There was dramatic improvement after high doses of steroids. MR findings 10 months later were normal. Thus, the diagnosis of the Tolosa-Hunt syndrome was established.

Essential trace element alterations in amyotrophic lateral sclerosis.

Although trace elements have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) for a long time, new evidence has connected familial ALS with the metalloenzyme copper-zinc superoxide dismutase, thus reinforcing the study of their metabolism. This work presents the results of serum and cerebrospinal fluid levels of copper, zinc, manganese and magnesium, by atomic absorption spectrophotometry. Statistically significant decreased cerebrospinal fluid and serum copper levels were found in patients compared to the control group (20.25 +/- 7.09 vs. 30.86 +/- 16.02 SD micrograms/l and 913.21 +/- 165.55 vs. 1020.17 +/- 197.76 SD micrograms/l) while serum manganese levels were found to be increased in patients (3.59 +/- 0.89 SD micrograms/l) compared to controls (3.03 +/- 1.23 SD micrograms/l). Zinc and magnesium levels were unchanged. Our findings indicate an essential trace element imbalance in the disease.

Serum levels of soluble intercellular adhesion molecule-1 and soluble endothelial leukocyte adhesion molecule-1 in Alzheimer's disease.

Serum soluble intercellular adhesion molecule-1 (s-ICAM-1) and soluble E-selectin (s-ELAM-1) were evaluated in 25 patients with Alzheimer's disease (AD), 54 patients with noninflammatory neurological diseases (NIND), and 15 control subjects. Patients with AD had a higher s-ICAM-1 level compared with the NIND patients and the control subjects (P< .001 and P< .04, respectively). The presence of high s-ICAM-1 values may be related to immunological processes involved in pathogenetic mechanisms of AD. The not statistically significant values of (s-ELAM-1), a glycoprotein considered an exclusive marker of endothelial activation, compared with the NIND patients and healthy subjects (P< .47 and P< .17, respectively), seem to suggest the neural rather than the endothelial s-ICAM origin in patients with AD.

Cortical atrophy detected by computed tomography in gasoline station attendants.

BACKGROUND: To evaluate the contribution of leaded gasoline in the presence of abnormal calcifications or cortical atrophy seen in computed tomographies (CT) of the head of occupationally exposed professionals working in the centre of Athens. METHODS: One hundred and twenty-two head CTs from gas station employees and traffic-exposed professionals (taxi and bus drivers) were analyzed for evidence of cortical atrophy or abnormal calcifications. Blood lead level (BLL) of these lead occupationally exposed groups was compared with 37 non-exposed subjects. RESULTS: All three occupationally exposed-to-lead groups had similar blood lead levels compared to the non-exposed group and within the currently accepted norms for lead. No abnormal calcifications were found. Cortical atrophy was more frequently seen in the gas station employees group using univariate and multivariate analysis. In the logistic regression model gas station employment had a stronger impact in developing cortical atrophy [odds ratio of 6.43 (1.46-28.3, 95% CI)] than BLL [odds ratio of 1.4 (1.01-2.05, 95% CI)]. CONCLUSIONS: These results show that employment in gasoline stations may be associated with detectable cortical atrophy in imaging studies and suggest the contribution of a leaded gasoline to its development.

Raeder's syndrome. Report of two cases.

Raeder's syndrome constitutes facial pain and ipsilateral stenosis of the palpebral fissure, miosis and enophthalmos. It is divided into two groups. Group I includes cases with parasellar cranial nerve involvement and group II without parasellar cranial nerve involvement. It is often difficult to distinguish group II of Raeder's syndrome from Horner's syndrome. The latter is painless and is accompanied by anidrosis of the ipsilateral half of the face. In fact Raeder's syndrome may be caused by any lesion affecting the post-ganglionic oculosympathetic fibers distal to the bifurcation of the common carotid artery. Serious lesions of the internal carotid artery (ICA) may be responsible for this syndrome. This paper deals with two cases of group II of Raeder's syndrome. In the first case, a 60-year-old man, the angiogram revealed an aneurysm of the extracranial part of the ICA just below its entrance into the calvarium. In the second case, a 42-year-old man, a dissective aneurysm of the ICA was found. Surgery was not attempted in either of our patients for different reasons. Their symptoms ameliorated quickly with medical treatment.

Trace elements, age, and sex in amyotrophic lateral sclerosis disease.

The statistical tests analysis of variance, analysis of covariance, correlation coefficient, Kolmogorov-Smirnov test, t-test, and Tukey test were applied to copper, magnesium, manganese, and zinc content in serum (S) and in cerebrospinal fluid (CSF) of controls and of a sporadic form of Amyotrophic Lateral Sclerosis (ALS) disease. This is carried out in order to evaluate statistically the possible relationships among the trace elements when ALS patients and controls are considered as independent groups, within sex groups and within age decades of both patients and control classes. A statistically significant difference between older controls (age > 40) and ALS patients (age > 40) for copper in CSF, copper in S, manganese in S, and zinc in CSF was found. Statistically significant correlation coefficients within the different classes formed for this study were observed. Within this pool, a correlation of patient group can differ statistically from the corresponding one of controls and vice versa. Thus, this correlation could be characteristic of the group from which is extracted, e.g., the correlation between copper in S and zinc in S, which is characteristic of ALS patients when considered as an independent group as well as members of the male patient class.

Blood lead levels of traffic- and gasoline-exposed professionals in the city of Athens.

During the past 10 y, blood lead levels in the population of Athens, Greece, have decreased steadily. This decrease has paralleled the reduction of tetraethyl lead in gasoline and the introduction of unleaded fuel. Blood lead levels and other parameters were studied in 42 gas-station employees, 47 taxi drivers, 47 bus drivers, and 36 controls, all of whom worked in Athens. The blood lead levels did not differ significantly among the four groups (5.64+/-1.7 microg/dl, 5.96+/-1.7 microg/dl, 5.88+/-1.3 microg/dl, and 5.76+/-1.7 microg/dl, respectively). Glutamic-oxaloacetic transaminase (i.e., aspartate aminotransferase) and glutamic-pyruvic transaminase (i.e., alanine aminotransferase) were elevated in gas-station employees, and the former was elevated in taxi drivers. Gas-station employees who smoked had higher blood lead levels than their nonsmoking counterparts. The absence of any difference in the blood lead levels of individuals for whom physical examinations were either normal or abnormal suggests that either lead was not the cause of increased blood lead levels or that its contribution may have been important in the past.

A normative study of the trail making test A and B in Greek adults.

The purpose of this study was to explore the effects of age and education on the performance of the Trail Making Test (TMT), and to provide normative data in the Greek population. The TMT was administered to 643 healthy participants. All participants satisfied the criteria excluding dementia and other medical, psychiatric, and neurological disorders. Statistical analysis revealed that, age, education, and general level of intelligence significantly influence individual performance. Performance on TMT, especially part B, decreases with increasing age and lower levels of education. Current norms of the Greek version of TMT represent a useful set of norms for clinical practice.