Christian Luckhaus

Amyloid β peptide ratio 42/40 but not Aβ42 correlates with phospho-Tau in patients with low- and high-CSF Aβ40 load

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 β peptides ending at the amino acid position of 42 (Aβx‐42 and Aβ1‐42) are widely accepted biomarkers of Alzheimer’s disease (AD). However, in subjects with constitutively high‐ or low‐CSF concentrations of total Aβ peptides (tAβ), the NDD interpretation might lead to erroneous conclusions as these biomarkers seem to correlate better with the total Aβ 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 Aβx‐40 concentrations and decreased Aβx‐42/x‐40 concentration ratio compared with the group of subjects with low CSF Aβx‐40 and normal Aβ ratio (p < 0.001 in both cases). Furthermore, we observed significantly decreased Aβ ratio (p < 0.01) in the group of subjects with APOE ε4 allele compared with the group of subjects without this allele. Surprisingly, patients with low‐Aβx‐40 and the decreased Aβ ratio characterized with decreased pTau181 (p < 0.05), and unaltered total Tau compared with the subjects with high Aβx‐40 and the Aβ ratio in the normal range. We conclude that the amyloid β concentration ratio should replace the ‘raw’ concentrations of corresponding Aβ peptides to improve reliability of the neurochemical dementia diagnosis.

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins α and β (sAPPα and sAPPβ) 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 examination⩾20 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 amyloidβ peptides, Tau and phospho-Tau. sAPPα and sAPPβ were measured with multiplexing method based on electrochemiluminescence. sAPPα and sAPPβ CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPPα and sAPPβ CSF concentrations in patients with NDD characteristic for Alzheimers disease (AD) compared to those with NDD negative results. sAPPα and sAPPβ highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPPα: cutoff, 117.4 ng ml−1, sensitivity, 68%, specificity, 85%, P<0.001; sAPPβ: cutoff, 181.8 ng ml−1, 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 sAPPα and sAPPβ might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease

Objective: To compare cued recall measures with other memory and nonmemory tests regarding their association with a biomarker profile indicative of Alzheimer disease (AD) in CSF among patients with mild cognitive impairment (MCI). Methods: Data were obtained by the German Dementia Competence Network. A total of 185 memory clinic patients fulfilling broad criteria for MCI (1 SD deficit in memory tests or in nonmemory tests) were assessed with an extended neuropsychological battery, which included the Free and Cued Selective Reminding Test (FCSRT), the word list learning task from the Consortium to Establish a Registry for Alzheimers Disease neuropsychological battery (CERAD-NP), and the Logical Memory (LM) paragraph recall test from the Wechsler Memory Scale–Revised. CSF was obtained from all patients. Results: A total of 74 out of 185 subjects with MCI (40%) had a CSF profile consistent with AD (Aβ1-42/tau ratio; CSF AD+ group). FCSRT measures reflecting both free and cued recall discriminated best between CSF AD+ and CSF AD− patients, and significantly improved CSF AD classification accuracy, as compared with CERAD delayed recall and LM delayed recall. Conclusions: 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.

Detection of changed regional cerebral blood flow in mild cognitive impairment and early Alzheimer's dementia by perfusion-weighted magnetic resonance imaging

The utility of perfusion-weighted magnetic resonance imaging (PW-MRI) for detecting changes in regional cerebral blood flow (rCBF) in patients with mild cognitive impairment (MCI) and early Alzheimers disease (AD) was evaluated. Thirteen cognitively normal (CN) elderly subjects, 35 mostly amnestic MCI subjects and 20 subjects with mild probable AD were enrolled. During i.v. injection of gadopentetate dimeglumine, a dynamic T2*-weighted single-shot EPI sequence was conducted using a 1.5-T scanner. Frontobasal (FROB), temporoparietal (TPAR), mesiotemporal (MTMP), anterior and posterior cingular (ACING, PCING), amygdala (AMYG), thalamus and cerebellar brain regions were studied. rCBF was computed from regional cerebral blood volume and arterial input function and normalised to white matter. Images were analysed by manually placed regions of interest using anatomical coregistration. Significant decreases of rCBF were detected in MCI vs. CN in MTMP (-23%), AMYG (-20%) and ACING (-15%) with no further decline in mild AD. In PCING hypoperfusion (-10%) was confined to AD. These hypoperfusional changes are a possible correlate of localised impairment of CNS function. In FROB no perfusion changes were observed between diagnostic groups, but hyperperfusion was observed in mild dementia stages, possibly reflecting functional compensatory mechanisms. These data suggest that PW-MRI detects specific changes in rCBF not only in AD, but also in amnestic MCI, a disorder suggested to largely represent a pre-dementia stage of AD. This method may thus be useful in both research and clinical applications to detect early functional brain changes in the pathogenesis of dementias.

Early and Differential Diagnosis of Dementia and Mild Cognitive Impairment Design and Cohort Baseline Characteristics of the German Dementia Competence Network

Background: The German Dementia Competence Network (DCN) has established procedures for standardized multicenter acquisition of clinical, biological and imaging data, for centralized data management, and for the evaluation of new treatments. Methods: A longitudinal cohort study was set up for patients with mild cognitive impairment (MCI), patients with mild dementia and control subjects. The aims were to establish the diagnostic, differential diagnostic and prognostic power of a range of clinical, laboratory and imaging methods. Furthermore, 2 clinical trials were conducted with patients suffering from MCI and mild to moderate Alzheimer’s Disease (AD). These trials aimed at evaluating the efficacy and safety of the combination of galantamine and memantine versus galantamine alone. Results: Here, we report on the scope and projects of the DCN, the methods that were employed, the composition and flow within the diverse groups of patients and control persons and on the clinical and neuropsychological baseline characteristics of the group of 2,113 subjects who participated in the observational and clinical trials. Conclusion: These data have an impact on the procedures for the early and differential clinical diagnosis of dementias, the current standard treatment of AD as well as on future clinical trials in AD.

Multicentre variability of MRI-based medial temporal lobe volumetry in Alzheimer's disease

Magnetic resonance imaging (MRI)-based volumetry of medial temporal lobe regions is among the best established biomarker candidates of Alzheimers disease (AD) to date. This study assessed the effect of multicentre variability of MRI-based hippocampus and amygdala volumetry on the discrimination between patients with Alzheimers disease (AD) and mild cognitive impairment (MCI) and on the association of morphological changes with ApoE4 genotype and cognition. We studied 113 patients with clinically probable AD and 150 patients with amnestic MCI using high-resolution MRI scans obtained at 12 clinical sites. We determined effect sizes of group discrimination and random effects linear models, considering multicentre variability. Hippocampus and amygdala volumes were significantly reduced in AD compared with MCI patients using data pooled across centres. Multicentre variability did not significantly affect the power to detect a volume difference between AD and MCI patients. Among cognitive measures, delayed recall of verbal and non-verbal material was significantly correlated with hippocampus and amygdala volumes. Amygdala and hippocampus volumes were not associated with ApoE4 genotype in AD or MCI. Our data indicate that multicentre acquisition of MRI data using manual volumetry is reliable and feasible for cross-sectional diagnostic studies, and they replicate essential findings from smaller scale monocentre studies.

Association of air pollution with cognitive functions and its modification by APOE gene variants in elderly women

BACKGROUND Epidemiological studies have shown effects of long-term exposure to air pollution on cardiovascular and respiratory health. However, studies investigating the effects of air pollution on cognition and brain function are limited. We investigated if neurocognitive functions are associated with air pollution exposure and whether apolipoprotein E (ApoE) alleles modify the association of air pollution exposure with cognition. METHODS We investigated 789 women from the SALIA cohort during the 22-year follow-up examination (2008-2009). Exposure to particulate matter (PM) size fractions and nitrogen oxides (NOx) were assigned to home addresses. Traffic indicators were used to assess residential proximity to high traffic load. Level of cognitive performance was assessed using the CERAD-Plus test. Air pollution effects on cognitive functioning were estimated cross-sectionally using adjusted linear regression models. RESULTS Air pollution was negatively associated with cognitive function and cognitive performance in the subtests for semantic memory and visuo-construction. Significant associations could be observed for figure copying with an interquartile range increase of NO2 (β=-0.28 (95%CI:-0.44;-0.12)), NOx (β=-0.25 (95%CI:-0.40;-0.09)), PM10 (β=-0.14 (95%CI:-0.26;-0.02)) and PM2.5 (β=-0.19 (95%CI:-0.36;-0.02)). The association with traffic load was significant in carriers of one or two ApoE ɛ4 risk alleles. CONCLUSION In this study of elderly women, markers of air pollution were associated with cognitive impairment in the visuospatial domain. The association of traffic exposure is significant in participants carrying the ApoE ε4 risk allele.

Hippocampal level of neural specific adenylyl cyclase type I is decreased in Alzheimer's disease.

Previous studies reported disruption of adenylyl cyclase (AC)-cyclic AMP (cAMP) signal transduction in brain of Alzheimers disease (AD). We also demonstrated that basal and stimulated AC activities in the presence of calcium and calmodulin (Ca(2+)/CaM) were significantly decreased in AD parietal cortex. In the present study, we examined the amounts of Ca(2+)/CaM-sensitive types I and VIII AC, and Ca(2+)/CaM-insensitive type VII AC in the postmortem hippocampi from AD patients and age-matched controls using immunoblotting. The specificities of the anti-type VII and VIII AC antibodies were confirmed by preabsorption with their specific blocking peptides. We observed a significant decrease in the level of type I AC and a tendency to decrease in the level of type VIII AC in AD hippocampus. On the other hand, the level of type VII AC showed no alteration between AD and controls. A body of evidence from the studies with invertebrates and vertebrates suggests that types I and VIII AC may play an essential role in learning and memory. Our finding thus firstly demonstrated that a specific disruption of the Ca(2+)/CaM-sensitive AC isoforms is likely involved in the pathophysiology in AD hippocampus.

Quantitative EEG in progressing vs stable mild cognitive impairment (MCI): results of a 1-year follow-up study

The study objective is to evaluate the use of qEEG data for the cross‐sectional differentiation of mild cognitive impairment (MCI) from mild Alzheimers disease (AD) and in the longitudinal prediction of cognitive decline in MCI.

Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer's type

Increased peripheral and central nervous system cortisol levels have been reported in Alzheimers disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline.