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Objective: To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD)., Methods: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005-2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI., Results: CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ(42). Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD., Conclusion: The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.

Objective: This is a study estimating diagnostic accuracy of CSF asialotransferrin to transferrin ratio measurement in eIF2B related disorders by using clinical evaluation and EIF2B mutation analysis as the reference standard. eIF2B-related disorder is a relatively common leukodystrophy with broad phenotypic variation that is caused by mutations in any of the five EIF2B genes. There is a need for a simple and clinically valid screening tool for physicians evaluating patients with an unclassified leukodystrophy., Methods: CSF two-dimensional gel (2DG) electrophoresis analyses to measure asialotransferrin to transferrin ratios were performed in 60 subjects including 6 patients with documented EIF2B gene mutations, patients with other types of leukodystrophy, and patients with no leukodystrophy., Results: All six patients with mutation proven eIF2B-related disease showed low to nearly undetectable amounts of asialotransferrin in their CSF when compared to 54 unaffected controls by CSF 2DG analyses in this study. eIF2B-like patients, with clinically similar presentations but no mutations in EIF2B1-5, were distinguished from patients with mutations in EIF2B1-5 by this biomarker. Patients with mutations in EIF2B1-5 had asialotransferrin/transferrin ratio levels significantly different from the group as a whole (p < 0.001). Using 8% asialotransferrin/transferrin ratio as a cutoff, this biomarker has a 100% sensitivity (95% CI = 52-100%) and 94% specificity (95% CI = 84-99%)., Conclusion: Decreased asialotransferrin/transferrin ratio in the CSF of patients with eIF2B-related disorder is highly sensitive and specific. This rapid (<48 hours) and inexpensive diagnostic tool for eIF2B-related disorders has the potential to identify patients with likely eIF2B-related disorder for mutation analysis.

Objective: To determine the usefulness of the 14-3-3 test in patients with dementia of various causes., Background: Recent reports have suggested that the detection of the 14-3-3 protein in the CSF of patients with Creutzfeldt--Jakob disease is a highly sensitive and specific marker of the disease that might be used as a diagnostic criterion. We examined the validity of this test when applied to a cohort of unselected patients prospectively examined for an ongoing dementing process., Methods: One hundred patients underwent an extensive neurologic examination for dementia, including a CSF 14-3-3 protein immunoblotting assay. Final clinical diagnoses were compared with the qualitative results of the test, and statistical measures of test validity were carried out., Results: We found a positive test in 14 of 100 patients, only two of whom had definite Creutzfeldt--Jakob disease. Positive results were found in patients with various degenerative dementias, including AD (4), frontotemporal dementia (2), and dementia with Lewy body (1), and in patients with vascular dementia (1), carcinomatous meningitis (1), and anoxic encephalopathy (1). In two other positive patients, the dementia could not be confidently classified. Sensitivity, specificity, and negative predictive value were fairly good, but positive predictive value was poor. Similar results were found independently of the disease duration. There was no correlation between intensity nor pattern of the 14-3-3 protein expression and diagnosis., Conclusions: The 14-3-3 test is not valid for discriminating between Creutzfeldt--Jakob disease and non-Creutzfeldt--Jakob disease in unselected patients with dementia. Positive results are found in various degenerative and secondary, prion-unrelated dementias.

Increased amounts of CSF pyruvate and lactate were found in patients with AD and patients with vascular dementia (VaD). In the AD group, CSF pyruvate values did not show any overlap with those obtained in controls; within the VaD group, the highest values were observed in possible VaD cases. A significant correlation between the severity of dementia and these biochemical parameters was also observed in both AD and possible VaD. The similarities of CSF pyruvate patterns observed in AD and possible VaD patients implicate a neurodegenerative component in this VaD subgroup.

There is a need for improvement of the diagnosis of vascular dementia (VaD). Today, the clinician has to rely on clinical examination, history, and, possibly, brain imaging to identify cerebrovascular damage and other signs of VaD. The clinical diagnosis of subcortical VaD may be difficult because the clinical manifestation of this disorder is often similar to that of Alzheimer disease. There are also mixed forms of the two disorders. Biochemical diagnostic markers, which reflect the pathogenetic processes in the brain, would add to the accuracy of the diagnosis. There are some interesting candidate markers: the cerebrospinal fluid (CSF)/serum albumin ratio could be used to identify blood-brain barrier damage to the small intracerebral vessels, CSF sulfatide to identify ongoing demyelination of the white matter, CSF neuron-specific enolase to identify ongoing neuronal degeneration, and CSF tau protein and CSF neurofilament light protein to identify ongoing axonal degeneration. None of these potential markers is specific to subcortical VaD, but together and used in conjunction with the conventional diagnostic workup, they may be of diagnostic value.

We investigated blood-brain barrier (BBB) function in relation to Alzheimer's disease (AD) and vascular dementia (VAD) in the very elderly. Sixty-five 85-year-old persons from a population-based sample were followed for 3 years; 29 were demented at age 85 (13 with AD, 14 with VAD, and 2 with other dementias), 7 developed dementia during follow-up, and 29 remained nondemented. CSF/serum albumin ratio was used as as a measure of BBB function. Dementia was defined according to the DSM-III-R, AD according to the NINCDS-ADRDA criteria, and VAD according to the NINDS-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) criteria. Mean CSF/serum albumin ratio was higher in all dementias (8.5 +/- 4.3; p = 0.007) and in the subtypes AD (8.9 +/- 5.3; p = 0.046) and VAD (8.7 +/- 3.5; p = 0.002) than in nondemented individuals (versus 6.5 +/- 2.0), but it was not related to dementia severity. Nondemented women at age 85 (n = 3) who developed dementia during the follow-up had a higher CSF/serum albumin ratio than those not developing dementia (10.4 +/- 2.0 versus 6.0 +/- 1.9; p = 0.007). Nondemented individuals lacking the apolipoprotein E epsilon3 allele (n = 4) had a higher CSF/serum albumin ratio (9.3 +/- 0.8 versus 6.6 +/- 2.1; p = 0.029) than other individuals. A relative BBB dysfunction is associated with both AD and VAD among very elderly individuals. This finding is possibly found early in the disease before the onset of clinical dementia.

Levels of alpha 1-antichymotrypsin (alpha 1-ACT) in cerebrospinal fluid (CSF) and serum from patients with probable Alzheimer disease (AD) of both early (e-AD) and late (l-AD) onset assessed by a competitive enzyme-linked immunosorbent assay were higher than those found in controls or in patients with vascular dementia (VD). A negative correlation between CSF levels of alpha 1-ACT and the stage of the disease was present in patients with both e-AD and l-AD. No difference in alpha 2-macroglobulin levels in CSF and serum from patients with e-AD, l-AD, VD, and nondemented controls was found. Serum concentrations of alpha 1-antitrypsin from l-AD subjects were within the normal range. Thus, increased levels of alpha 1-ACT in CSF and serum were specifically associated with AD, and the detection of this serpin in CSF may be useful in monitoring the progression of the disease.