Neurochemical dementia diagnostics (NDD) can significantly improve the clinically based categorization of patients with early dementia disorders, and the cerebrospinal fluid (CSF) concentrations of amyloid b peptides ending at the amino acid position of 42 (Abx-42 and Ab1-42) are widely accepted biomarkers of Alzheimer's disease (AD). However, in subjects with constitutively high-or low-CSF concentrations of total Ab peptides (tAb), the NDD interpretation might lead to erroneous conclusions as these biomarkers seem to correlate better with the total Ab load than with the pathological status of a given patient in such cases. In this multicenter study, we found significantly increased CSF concentrations of phosphorylated Tau (pTau181) and total Tau in the group of subjects with high CSF Abx-40 concentrations and decreased Abx-42/x-40 concentration ratio compared with the group of subjects with low CSF Abx-40 and normal Ab ratio (p < 0.001 in both cases). Furthermore, we observed significantly decreased Ab ratio (p < 0.01) in the group of subjects with APOE e4 allele compared with the group of subjects without this allele. Surprisingly, patients with low-Abx-40 and the decreased Ab ratio characterized with decreased pTau181 (p < 0.05), and unaltered total Tau compared with the subjects with high Abx-40 and the Ab ratio in the normal range. We conclude that the amyloid b concentration ratio should replace the 'raw' concentrations of corresponding Ab peptides to improve reliability of the neurochemical dementia diagnosis.

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Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with MCI. This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria.

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins a and b (sAPPa and sAPPb) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examinationX20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloidb peptides, Tau and phospho-Tau. sAPPa and sAPPb were measured with multiplexing method based on electrochemiluminescence. sAPPa and sAPPb CSF concentrations correlated with each other with very high correlation ratio (R = 0.96, P < 0.001). We observed highly significantly increased sAPPa and sAPPb CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPPa and sAPPb highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPPa: cutoff, 117.4 ng ml À1 , sensitivity, 68%, specificity, 85%, P < 0.001; sAPPb: cutoff, 181.8 ng ml À1 , sensitivity, 75%, specificity, 85%, P < 0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPPa and sAPPb might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

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Schizophrenia is a chronic illness of heterogenous biological origin. We hypothesized that, similar to chronic progressive brain conditions, persistent functional disturbances of neurons would result in disturbed proteostasis in the brains of schizophrenia patients, leading to increased abundance of specific misfolded, insoluble proteins. Identification of such proteins would facilitate the elucidation of molecular processes underlying these devastating conditions. We therefore generated antibodies against pooled insoluble proteome of post-mortem brains from schizophrenia patients in order to identify unique, disease-specific epitopes. We successfully identified such an epitope to be present on collapsin-response mediator protein 1 (CRMP1) in biochemically purified, insoluble brain fractions. A genetic association analysis for the CRMP1 gene in a large Finnish population cohort (n = 4651) corroborated the association of physical and social anhedonia with the CRMP1 locus in a DISC1 (Disrupted-in-schizophrenia 1)-dependent manner. Physical and social anhedonia are heritable traits, present as chronic, negative symptoms of schizophrenia and severe major depression, thus constituting serious vulnerability factors for mental disease. Strikingly, lymphoblastoid cell lines derived from schizophrenia patients mirrored aberrant CRMP1 immunoreactivity by showing an increase of CRMP1 expression, suggesting its potential role as a blood-based diagnostic marker. CRMP1 is a novel candidate protein for schizophrenia traits at the intersection of the reelin and DISC1 pathways that directly and functionally interacts with DISC1. We demonstrate the impact of an interdisciplinary approach where the identification of a disease-associated epitope in post-mortem brains, powered by a genetic association study, is rapidly translated into a potential blood-based diagnostic marker.

qEEG revealed decreased alpha activity in progressing MCI and mild AD prior to an increase of slow wave activity, which typically occurs in advancing AD. This finding may reflect an affection of thalamo-cortical relay activity and cortical connectivity in the early disease course of AD. Reduced alpha activity in MCI subjects at baseline may have prognostic value regarding future cognitive decline.