George P. Paraskevas

The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.

The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)‐42, total‐tau (T‐tau), and phosphorylated‐tau (P‐tau) demonstrate good diagnostic accuracy for Alzheimers disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimers Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch‐to‐batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.

Increased Cerebrospinal Fluid Tau Protein in Multiple Sclerosis

Axonal damage is now being recognized as a common finding in multiple sclerosis (MS) lesions and a cause of irreversible neurological damage. Attempts to identify markers of early axonal damage are of great significance. This prompted us to examine the microtubule-associated protein tau in the cerebrospinal fluid (CSF) of patients with MS vs. controls. Tau was measured by double antibody sandwich ELISA. Increased CSF tau levels were found in MS as compared to controls (medians 249.6 and 135 pg/ml respectively, p < 0.001). Half of the MS patients presented with levels above the upper limit of the controls. A significant increase vs. controls was found in both relapsing-remitting and progressive subtypes. These data may indicate axonal impairment in a subpopulation of MS patients and may provide a tool for the estimation of axonal damage during life.

Diagnostic value of CSF biomarker profile in frontotemporal lobar degeneration.

BackgroundCerebrospinal fluid (CSF) biomarkers have been increasingly studied in dementia clinical and differential diagnosis. MethodsWe assessed levels of total tau protein (τT), tau phosphorylated at threonine 181 (τP-181), and β-amyloid1-42 (Aβ42) in 34 patients with frontotemporal lobar degeneration (FTLD), 76 Alzheimer disease (AD) cases, and 93 controls (CTRL). Double sandwich enzyme-linked immunosorbent assays (Innogenetics) were used for measurements. ResultsTotal τ was significantly increased and Aβ42 decreased in FTLD and AD patients as compared with CTRL. CSF τP-181 levels were significantly increased only in AD. The τT/Aβ42 ratio successfully discriminated FTLD from CTRL with a 86.7% specificity and 80.6% sensitivity, whereas the τT alone was more specific (95.7%) but less sensitive (64.75%). For the discrimination of FTLD from AD, τT/Aβ42 ratio was better (90.3% sensitivity and 64.5% specificity) compared with the other biomarkers alone or in combination, whereas τP-181 was less sensitive but more specific (68.4% and 85.7%, respectively). Subtype analysis revealed that the most AD-like profile of biomarkers were observed in FTLD with motor neuron signs, whereas the most non-AD profile were observed in patients with primary progressive aphasia. ConclusionsCombined analysis of CSF biomarkers may be useful for the best possible antemortem discrimination of FTLD from AD.

Association study of cholesterol-related genes in Alzheimer’s disease

Alzheimer’s disease (AD) is a genetically complex disorder, and several genes related to cholesterol metabolism have been reported to contribute to AD risk. To identify further AD susceptibility genes, we have screened genes that map to chromosomal regions with high logarithm of the odds scores for AD in full genome scans and are related to cholesterol metabolism. In a European screening sample of 115 sporadic AD patients and 191 healthy control subjects, we analyzed single nucleotide polymorphisms in 28 cholesterol-related genes for association with AD. The genes HMGCS2, FDPS, RAFTLIN, ACAD8, NPC2, and ABCG1 were associated with AD at a significance level of P ≤ 0.05 in this sample. Replication trials in five independent European samples detected associations of variants within HMGCS2, FDPS, NPC2, or ABCG1 with AD in some samples (P = 0.05 to P = 0.005). We did not identify a marker that was significantly associated with AD in the pooled sample (n = 2864). Stratification of this sample revealed an APOE-dependent association of HMGCS2 with AD (P = 0.004). We conclude that genetic variants investigated in this study may be associated with a moderate modification of the risk for AD in some samples.

Interleukin-12 is reduced in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia

UNLABELLED Interleukin-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, such as Interferon-gamma and Tumor Necrosis Factor-alpha. There is little information about the involvement of IL-12 in the pathophysiology of Alzheimers disease (AD) and other tauopathies. OBJECTIVES The objective of our study was to assess the role of IL-12 as a potential marker of immune reactions in patients with AD and frontotemporal dementia (FTD). PATIENTS AND METHODS We measured by immunoassay cerebrospinal fluid (CSF) IL-12 levels in 19 patients with AD and 7 patients with FTD in comparison with CSF IL-12 levels in 30 patients with non-inflammatory neurological diseases served as neurological control patients (NCTRL). IL-12 levels were correlated with age, age of disease onset, disease duration, MMSE score, and rate of dementia progression. Abeta42 and Total tau (tau(T)) levels in CSF were also measured. RESULTS Patients with AD had significantly lower CSF IL-12 levels compared with NCTRL patients (p<0.001). Patients with FTD had also lower CSF IL-12 levels compared with NCTRL patients (p<0.05). Age, sex, disease duration and MMSE score did not affect IL-12 levels in any of the groups. In AD a significant positive correlation was noted between IL-12 levels and tau(T) levels (Rs=0.46, p=0.048). CONCLUSIONS Our findings may suggest a reduced inflammatory reaction during the course of AD and FTD. A neurotrophic role of IL-12 and other proinflammatory cytokines cannot be excluded.

The diagnostic value of cerebrospinal fluid tau protein in dementing and nondementing neuropsychiatric disorders

Cerebrospinal fluid (CSF) total tau protein (τT) is increased in Alzheimer’s disease (AD) and may be of some help in the diagnostic work-up of demented patients. The aim of the present study was to investigate the diagnostic aid and the additional help (over that of clinical criteria) of τT in different clinical situations. Double-sandwich enzyme-linked immunosorbent assay was used to quantify τT in 61 healthy controls and 241 patients with various neuropsychiatric diseases. Our results suggest that CSF τT offers significant additional information over that of clinical criteria of AD, for the discrimination of AD from normal aging, depression, synucleinopathy, and possibly vascular dementia. However, for the differential diagnosis from frontotemporal dementia, corticobasal ganglionic degeneration, and secondary dementia, the diagnostic value is inadequate.

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 diagnostic value of CSF α-synuclein in the differential diagnosis of dementia with Lewy bodies vs. normal subjects and patients with Alzheimer's disease.

The detection of α-synuclein (α-syn) in the cerebrospinal fluid (CSF) of patients with synucleinopathy has yielded promising but inconclusive results. The aim of the present study was to determine the diagnostic value of α-syn as a biological marker for Dementia with Lewy bodies (DLB) vs. normal subjects and patients with Alzheimer’s disease (AD), after strict control of several recognized confounders. Sixteen patients with DLB, 18 patients with AD and 22 age- and sex-matched normal controls (CTRL) were recruited. The levels of total α-syn in CSF were measured using a novel enzyme-linked immunosorbent assay. There was a significant increase of CSF α-syn levels in DLB patients as compared to the CTRL and AD groups (P= 0.049 and 0.01 respectively). ROC analysis revealed that increased α-syn was 81.8% specific for the discrimination of DLB vs. CTRL and 90% vs. AD. However, sensitivity was lower (56.2 % and 50% respectively). These findings provide evidence for a possible diagnostic role of α-syn as a surrogate biomarker for DLB.

Plasma levels of antioxidant vitamins C and E are decreased in vascular parkinsonism.

Oxidative stress is an important mechanism of cell death in Parkinsons disease (PD) and brain ischemia. Vitamins C, E and A are important antioxidants and deficiency of these agents has been implicated in the mechanisms of atherosclerosis. We measured the levels of the above antioxidant vitamins in 44 patients with PD, 12 patients with vascular parkinsonism (VP), 11 patients with other parkinsonism syndromes of various causes and 39 controls. Vitamin A levels did not differ between groups. Vitamins C and E were found decreased in VP, while they were normal in PD indicating low levels of antioxidant vitamins in VP and stressing the necessity of maintaining sufficient dietary intake of these agents in the elderly.

Plasma homocysteine levels in patients with multiple sclerosis in the Greek population.

Background: In recent years, there has been increasing interest in the role of plasma homocysteine (Hcy) as a possible risk factor for several diseases of the central nervous system. The aim of this study was to determine the plasma levels of Hcy in a group of multiple sclerosis (MS) patients from a Greek population and the possible correlation with age, disability status, activity or duration of disease, sex, and treatment. Methods: The MS group that was studied consisted of 46 patients and a total of 42 healthy individuals served as a control group. Plasma Hcy levels were determined by means of high‐performance liquid chromatography coupled with fluorescence detection, after precolumn derivatization with 4‐Fluoro‐7‐aminosulfonylbenzofurazan (ABD‐F). Results: Statistical analysis revealed that, in the MS patients, Hcy levels were not significantly different as compared to those in the controls. Men presented with higher Hcy levels than women in the MS group; however, age, disease subtype, disease duration, relapse rate, and Expanded Disability Status Scale score/Multiple Sclerosis Severity Score did not significantly affect Hcy levels in MS patients. Conclusion: The preliminary data suggest that Hcy levels were not elevated in our sample of Greek MS patients, which does not support previous findings of a significant correlation between elevated serum Hcy levels and MS. Further studies to establish a possible association between MS and Hcy levels in the context of different ethnic groups with different habits are needed.