Alzheimer Disease: Kornhuber J

Kornhuber J. · Klinik mit Poliklinik für Psychiatrie und Psychotherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen. · Fortschr Neurol Psychiatr. · Pubmed #15942860 No free full text.

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Kornhuber J. · No affiliation provided · Fortschr Neurol Psychiatr. · Pubmed #15472777 No free full text.

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Kornhuber J. · No affiliation provided · Fortschr Neurol Psychiatr. · Pubmed #15095174 No free full text.

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Kornhuber J. · No affiliation provided · Nervenarzt. · Pubmed #12078016 No free full text.

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Weih M, Abu-Omar K, Esselmann H, Gelbrich G, Lewczuk P, Rütten A, Wiltfang J, Kornhuber J. · Psychiatrische und Psychotherapeutische Klinik, Universitätsklinikum Erlangen. · Fortschr Neurol Psychiatr. · Pubmed #19283649 No free full text.

Abstract: There is accumulating evidence from animal and epidemiologic studies that physical exercise is neuroprotective in healthy animals and humans and can prevent cognitive decline in chronic neurodegenerative processes like Alzheimer's dementia. However, data from well-designed interventional, randomized non-pharmacologic trials is lacking in contrast to other areas of medicine like prevention of hypertension, diabetes or the antipsychotic-associated metabolic syndrome. The demonstration of a potential positive effect of physical exercise on preventing dementia using a controlled study design would represent a significant progress in the prevention of dementia and public health, especially as long as other treatments for dementia prevention are lacking.

Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Brain. · Pubmed #17018549 links to  free full text

Abstract: Alzheimer's disease is an age-related progressive neurodegenerative disorder with an enormous unmet medical need. It is the most common form of dementia affecting approximately 5% of adults over 65 years. In view of our ageing society the number of patients, as well as the economical and social impact, is expected to grow dramatically in the future. Currently available medications appear to be able to produce moderate symptomatic benefits but not to stop disease progression. The search for novel therapeutic approaches targeting the presumed underlying pathogenic mechanisms has been a major focus of research and it is expected that novel medications with disease-modifying properties will emerge from these efforts in the future. In this review, currently available drugs as well as novel therapeutic strategies, in particular those targeting amyloid and tau pathologies, are discussed.

Wiltfang J, Lewczuk P, Riederer P, Grünblatt E, Hock C, Scheltens P, Hampel H, Vanderstichele H, Iqbal K, Galasko D, Lannfelt L, Otto M, Esselmann H, Henkel AW, Kornhuber J, Blennow K. · Molecular Neurobiology Lab, Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. · World J Biol Psychiatry. · Pubmed #16156480 No free full text.

Abstract: Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Abeta peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.

Bleich S, Römer K, Wiltfang J, Kornhuber J. · Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Germany. · Int J Geriatr Psychiatry. · Pubmed #12973748 No free full text.

Abstract: Glutamate is the most important excitatory neurotransmitter in the central nervous system. In the process, glutamate fulfills numerous physiological functions, but also plays an important role in the pathophysiology of different neurological and psychiatric diseases, especially when an imbalance in glutamatergic neurotransmission occurs. Under certain conditions, glutamate has a toxic action resulting from an activation of specific glutamate receptors, which leads to acute or chronic death of nerve cells. Such mechanisms are currently under discussion in acute neuronal death within the context of hypoxia, ischaemia and traumas, as well as in chronic neurodegenerative or neurometabolic diseases, idiopathic parkinsonian syndrome, Alzheimer's dementia and Huntington's disease. It is hoped that glutamate antagonists will lead to novel therapies for these diseases, whereby the further development of glutamate antagonists for blocking disease-specific subtypes of glutamate receptors may be of major importance in the future.

Wiltfang J, Esselmann H, Maler JM, Bleich S, Hüther G, Kornhuber J. · Department of Psychiatry, Georg August University, Göttingen, Germany. · Gerontology. · Pubmed #11287729 No free full text.

Abstract: Over the past few years, molecular biological research has considerably deepened our understanding of the pathophysiological basis of Alzheimer's dementia (AD). Although different genetic origins of the disease have been identified, all of the findings point to a common terminal sequence in familial AD. This consists of an increased production of beta-amyloid peptides from beta-amyloid precursor protein. For the cases of sporadic AD, which far outweigh the number of cases of familial AD, an impaired catabolism of the beta-amyloid peptides may also be pathophysiologically decisive according to the latest findings. Research into the molecular level of AD makes it possible to identify points of attack for rational drug treatment of the disease, while molecular markers of AD are increasingly being used as a part of early and differential neurochemical diagnostics.

Maler JM, Spitzer P, Lewczuk P, Kornhuber J, Herrmann M, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Mol Psychiatry. · Pubmed #17033629 No free full text.

Abstract: Hematopoietic stem cells contribute to mammalian brain tissue regeneration by transdifferentiation processes. We found decreased counts of circulating CD34+ cells in early Alzheimer's dementia (AD; P = 0.01), which significantly correlated with age (r = -0.661; P = 0.001), cerebrospinal fluid beta-amyloid (Abeta)1-42 (r = -0.467; P = 0.025) and most pronounced the Abeta42/40 ratio (r = -0.688; P = 0.005). Our data suggest a deficient regenerative hematopoietic support for the central nervous system in early AD.

Froelich L, Gertz HJ, Heun R, Heuser I, Jendroska K, Kornhuber J, Kurz A, Mueller-Thomsen T, Ries F, Waechtler C, Metz M, Goebel C. · Division of Geriatric Psychiatry, Central Institute for Mental Health Mannheim, University of Heidelberg, Heidelberg, Germany. · Dement Geriatr Cogn Disord. · Pubmed #15084792 No free full text.

Abstract: This multicenter open-label clinical trial was designed to investigate the safety and efficacy of donepezil, a selective acetylcholinesterase inhibitor, in the treatment of Alzheimer's disease (AD) in routine clinical practice in Germany. A total of 237 patients with mild-to-moderate AD were treated with donepezil for 24 weeks, 186 completed the study according to the protocol. In the completer group, mean MMSE score for efficacy showed an improvement from baseline of +1.6 points at week 12 (95% CI +1.1 to +2.1) and of +1.1 points at week 24 (95% CI +0.5 to +1.7). In more than 80% of the patients, global tolerability was rated to be very good or good. There were only insignificant effects on ECG parameters. This study confirms the results obtained in previous double-blind trials, which showed that donepezil is effective and well tolerated in patients with mild-to-moderately severe AD.

Lewczuk P, Esselmann H, Groemer TW, Bibl M, Maler JM, Steinacker P, Otto M, Kornhuber J, Wiltfang J. · Department of Psychiatry and Psychotherapy (PL, TWG, JMM, JK, JW), University of Erlangen-Nuremberg, Erlangen, Germany. · Biol Psychiatry. · Pubmed #15023581 No free full text.

Abstract: BACKGROUND: The advent of new therapeutic avenues for Alzheimer's disease (AD) calls for an improved early and differential diagnosis. METHODS: With surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), cerebrospinal fluid from patients with AD (n = 10) and nondemented control subjects (n = 9) was studied. RESULTS: Molecular mass signals were observed corresponding to three novel amyloid beta (Abeta) peptides that have not previously been described, in addition to those previously known, with molecular masses of 4525.1 d, 4846.8 d, and 7755.8 d. The signal-to-noise ratios (S/NR) of Abeta(4525.1) and Abeta(7758.8+2H) were significantly decreased in AD [Abeta(4525.1): median 2.2 and 4.3 in AD and control subjects, respectively, p <.01; Abeta(7758.8+2H): median 1.0 and 14.0 in AD and control subjects, respectively, p <.01], whereas the S/NR of Abeta(4846.8) was significantly increased in AD (median 3.6 and 2.5 in AD and control subjects, respectively, p <.05). The S/NR of two known AD biomarkers, Abeta1-42 and Abeta1-40, expectedly turned out to be significantly decreased (p <.01) and unaltered in AD, respectively. A moderate and highly significant correlation was observed between S/NR of Abeta1-42 and Abeta42 concentration as measured with enzyme-linked immunosorbent assay (R =.67, p <.01). CONCLUSIONS: We report evidence of three novel amyloid beta peptides that might play an important role in the diagnosis and pathophysiology of Alzheimer's disease.

Jessen F, Gür O, Block W, Ende G, Frölich L, Hammen T, Wiltfang J, Kucinski T, Jahn H, Heun R, Maier W, Kölsch H, Kornhuber J, Träber F. · Department of Psychiatry, University of Bonn, Germany. · Neurology. · Pubmed #19451528 No free full text.

Abstract: OBJECTIVE: The need for biological markers of Alzheimer disease (AD) is constantly increasing. Proton magnetic resonance spectroscopy ((1)H-MRS) studies have provided consistent evidence for a reduction of the neuronal marker N-acetylaspartate (NAA) in patients with AD. Within the German Competence Network on Dementia, we conducted a (1)H-MRS study in patients with mild dementia and mild cognitive impairment (MCI) at four sites to investigate the multicenter feasibility of (1)H-MRS. METHODS: In total, 130 patients with dementia (98 AD, 32 non-AD), 136 subjects with MCI (70 of AD type, 66 of non-AD type), and 45 unimpaired control subjects were included. Single-volume (1)H-MRS of the left medial temporal lobe was performed at long and short echo times. Metabolites were quantified and metabolic ratios were determined. RESULTS: We found a significant reduction of NAA concentration in patients with AD as compared to healthy volunteers and compared to patients with MCI of AD type. NAA/Cr (creatine/phosphocreatine) was also lower in patients with AD compared to control subjects. NAA, choline compounds, and Cr were lower in patients with AD compared to patients with non-AD dementia. CONCLUSIONS: We demonstrated the multicenter feasibility of proton magnetic resonance spectroscopy ((1)H-MRS) of the medial temporal lobe in mild dementia and mild cognitive impairment, which is a prerequisite for the application of (1)H-MRS in large-scale clinical trials. Since the concentration measures of the metabolites are adjusted for brain tissue volume, these findings are indicators of biochemical pathology beyond brain atrophy.

Welge V, Fiege O, Lewczuk P, Mollenhauer B, Esselmann H, Klafki HW, Wolf S, Trenkwalder C, Otto M, Kornhuber J, Wiltfang J, Bibl M. · Klinik für Psychiatrie und Psychotherapie, Universität Duisburg-Essen, Rheinische Kliniken Essen, Essen, Germany. · J Neural Transm. · Pubmed #19142572 No free full text.

Abstract: Cerebrospinal fluid (CSF) concentrations of amyloid-beta (Abeta) 1-38, 1-40, 1-42, total-tau and phospho-tau in samples from 156 patients with Alzheimer's disease (AD) (n = 44), depressive cognitive complainers (DCC, n = 25) and various other forms of non-Alzheimer dementias (NAD, n = 87) were analyzed by electrochemiluminescence and enzyme linked immunosorbent assay, respectively. A significant decrease of CSF Abeta1-42 was the most powerful single marker for differentiation of AD from DCC, yielding accuracies of beyond 85%. Increased p-tau and the ratio Abeta1-42/Abeta1-38 yielded accuracies of beyond 80 and 85%, respectively, to discriminate AD versus NAD. Combining p-tau with Abeta1-42/Abeta1-38 resulted in a sensitivity of 94% for detection of AD and 85% specificity for excluding NAD. Decreased CSF Abeta1-42 represents a core biomarker for AD. The lack of specificity for exclusion of NAD can be most effectively compensated by the ratio Abeta1-42/Abeta1-38. The ratio Abeta1-42/Abeta1-38/p-tau powerfully discriminates AD versus NAD and fulfils the accuracy requirements for an applicable screening and differential diagnostic AD biomarker.

Graessel E, Viegas R, Stemmer R, Küchly B, Kornhuber J, Donath C. · Department of Medical Psychology and Medical Sociology, Psychiatric University Clinic Erlangen, Germany. · Int Psychogeriatr. · Pubmed #18925975 No free full text.

Abstract: BACKGROUND: In the absence of an easily applicable performance test for making valid measurements of fundamental activities of daily living (ADL) in dementia patients, this study reports the development of an ADL performance test which constitutes both a reliable and a valid measurement of the relevant autonomous areas of everyday activities for dementia patients. METHODS: The Erlangen Test of Activities of Daily Living (E-ADL-Test) consists of five items: pouring a drink, cutting a piece of bread, opening a small cupboard, washing hands and tying a bow. Each test item underwent standardized evaluation on a scale of 0 to 6. To determine retest reliability each assessment was repeated at two-weekly intervals. The Global Deterioration Scale, Mini-mental State Examination (MMSE) and Nurses' Observations Scale for Geriatric Patients (NOSGER) were used to assess construct validity. Spearman's rank correlation coefficient was applied. Forty-six patients (42 women and 4 men) with clinically diagnosed dementia, who were resident in nursing homes, took part in the validation study. Their average age was 86. RESULTS: The E-ADL-Test revealed good inter-individual differentiation ability, particularly in cases of moderate to severe dementia. Cronbach's alpha was 0.77, retest reliability 0.73. The correlation coefficients were -0.47 with GDS, 0.60 with NOSGER and 0.72 with MMSE. CONCLUSIONS: The E-ADL-Test is a suitable performance test for measuring activities of daily living as it is easy to use, reliable, valid and well accepted.

Grässel E, Bleich S, Meyer-Wegener K, Schmid U, Kornhuber J, Prokosch HU. · Die Institutsangaben sind am Ende des Beitrags gelistet. · Psychiatr Prax. · Pubmed #18924061 No free full text.

Abstract: OBJECTIVE: What significance has the Internet as a source of information for family caregivers of dementia patients? METHODS: In Middle Franconia (Germany), 391 family caregivers were requested to participate in a questionnaire-based postal survey about the significance of the Internet and other sources of information on dementia. The family caregivers in question were the relatives of patients of the Memory Clinic at Erlangen University Psychiatric Hospital, members of the Alzheimer's Society of Middle Franconia or the Nuremberg Family Counselling Society. RESULTS: Younger and better-educated family caregivers more often own a computer with Internet access than older ones. The Internet is in 4th place on their list of sources of information. Although doctors are by far the most important source, counselling centres and literature are rated only just before the Internet. CONCLUSIONS: The Internet is particularly significant for the younger better-educated family caregivers, independent of gender, as a source of information on the diagnosis and treatment of dementia.

Maler JM, Spitzer P, Klafki HW, Esselmann H, Lewczuk P, Kornhuber J, Herrmann M, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany. · J Neuroimmunol. · Pubmed #18824266 No free full text.

Abstract: The presence of cells of the mononuclear phagocyte lineage surrounding neuritic and vascular beta-amyloid (Abeta) plaques is a hallmark of Alzheimer's disease (AD) neuropathology. The fractional Abeta peptide patterns released by human mononuclear phagocyte (MNP), lymphocyte and PBMC cultures were assessed by Abeta-SDS-PAGE/immunoblot and compared with the Abeta patterns in neuronal supernatants, in cerebrospinal fluid (CSF), and plasma. MNP released substantial amounts of Abeta peptides and the Abeta pattern contrasted with that in neuronal supernatants, CSF and plasma by reduced Abeta(1-42) and increased proportions of N-truncated Abeta species. MNP derived from early AD patients released significantly more total Abeta peptides than age-matched controls. The proportion of Abeta(1-42) was not altered.

Kölsch H, Jessen F, Wiltfang J, Lewczuk P, Dichgans M, Kornhuber J, Frölich L, Heuser I, Peters O, Schulz JB, Schwab SG, Maier W. · Department of Psychiatry, University of Bonn, Bonn, Germany. · Neurosci Lett. · Pubmed #18541377 No free full text.

Abstract: SORL1 gene variants were described as risk factors of Alzheimer's disease (AD). We investigated the association of four SORL1 variants with CSF levels of Abeta42 and Abeta40 in 153 AD patients recruited from a multicenter study of the German Competence Net Dementias. Only one SORL1 SNP was associated with altered Abeta42 levels in the single marker analysis (SNP21: p=0.011), the other SNPs did not show an association with Abeta42 or Abeta40 CSF levels. Haplotype analysis identified a three marker SORL1 haplotype consisting of SNP19 T-allele, SNP21 G-allele and SNP23 A-allele (T/G/A) which was associated with reduced Abeta42 CSF levels in AD patients (p=0.003). Abeta40 levels were also lower in carriers of this haplotype; however, this did not reach statistical significance (p=0.15). We found a SORL1 haplotype which was associated with CSF levels of amyloid-beta cleavage products, measured as altered levels of Abeta42. Thus our data suggest that SORL1 gene variants might influence AD pathology.

Maler JM, Spitzer P, Klafki HW, Esselmann H, Bibl M, Lewczuk P, Kornhuber J, Herrmann M, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany. · Brain Behav Immun. · Pubmed #18511234 No free full text.

Abstract: Cells of the mononuclear phagocyte system are closely associated with vascular and neuritic beta-amyloid deposits in Alzheimer's disease. Using one-dimensional and newly developed two-dimensional Abeta-SDS-PAGE Western immunoblot techniques (1D/2D-Abeta-WIB) we investigated the patterns of Abeta peptides released by primary non-adherent and adherence-activated human mononuclear phagocytes in vitro. An overall increase of total released Abeta peptides (Abeta(total)) was observed in adherence-activated mononuclear phagocyte cultures. 2D-Abeta-WIB revealed that the proportion of Abeta(1-40) decreased significantly to 50.2+/-5.4% (n=10) of Abeta(total) compared to 65.9+/-5.6% (n=7) in non-adherent cultures (p<0.0001, t=5.82). Abeta(1-42) accounted for only 3.0+/-2.1% of Abeta(total) and its proportion did not change significantly upon adherence (2.8+/-0.5% of Abeta(total)). In adherence-activated cultures we detected pronounced shifts in the fractional pattern of released Abeta peptides in favour of N-truncated species. The second most prominent Abeta peptide accounted for as much as 12.7+/-3.0% of Abeta(total) (2.0+/-1.2% in non-adherent cultures; p<0.0001, t=9.00) and was identified as Abeta(2-40) by comigration with a synthetic peptide and by N-terminal-specific antibodies. A strong increase of a further Abeta immunoreactive spot migrating at pI 5.45 was observed. It accounted for 9.2+/-1.7% of Abeta(total) as compared to 1.0+/-0.9% in non-adherent cultures (p<0.0001, t=11.61) and presumably represented a variant of Abeta(2-40) as determined by C-terminal Abeta(40)-specific immunoprecipitation and N-terminal-specific immunodetection. Thus, mononuclear phagocytes might be one source of the N-truncated Abeta peptides regularly found in human plasma and are less likely to contribute substantially to plasma Abeta(1-42).

Maler JM, Klafki HW, Paul S, Spitzer P, Groemer TW, Henkel AW, Esselmann H, Lewczuk P, Kornhuber J, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Proteomics. · Pubmed #17924594 No free full text.

Abstract: The detailed analysis of beta-amyloid (Abeta) peptides in human plasma is still hampered by the limited sensitivity of available mass spectrometric methods and the lack of appropiate ELISAs to measure Abeta peptides other than Abeta(1-38), Abeta(1-40), and Abeta(1-42). By combining high-yield Abeta immuno- precipitation (IP), IEF, and urea-based Abeta-SDS-PAGE-immunoblot, at least 30 Abeta-immuno-reactive spots were detected in human plasma samples as small as 1.6 mL. This approach clearly resolved Abeta peptides Abeta(1-40), Abeta(1-42), Abeta(1-37), Abeta(1-38), Abeta(1-39), the N-truncated Abeta(2-40), Abeta(2-42), and, for the first time, also Abeta(1-41). Relative quantification indicated that Abeta(1-40) and Abeta(1-42) accounted for less than 60% of the total amount of Abeta peptides in plasma. All other Abeta peptides appear to be either C-terminally or N-terminally truncated forms or as yet uncharacterized Abeta species which migrated as trains of spots with distinct pIs. The Abeta pattern found in cerebrospinal fluid (CSF) was substantially less complex. This sensitive method (2-D Abeta-WIB) might help clarifying the origin of distinct Abeta species from different tissues, cell types, or intracellular pools as well as their amyloidogenicity. It might further help identifying plasma Abeta species suitable as biomarkers for the diagnosis of Alzheimer's disease (AD).

Bibl M, Esselmann H, Mollenhauer B, Weniger G, Welge V, Liess M, Lewczuk P, Otto M, Schulz JB, Trenkwalder C, Kornhuber J, Wiltfang J. · Department of Psychiatry University of Goettingen, von-Siebold-Str, Goettingen, Germany. · J Neurochem. · Pubmed #17662050 No free full text.

Abstract: Blood-based tests for the differential diagnosis of Alzheimer's disease (AD) are under intensive investigation and have shown promising results with regard to Abeta40 and Abeta42 peptide species in incipient AD. Moreover, plasma Abeta40 was suggested as an independent cerebrovascular risk factor candidate. These considerations prompted us to analyse a total of 72 plasma samples in vascular dementias (VAD, n = 15), AD with cerebrovascular disease (AD with CVD, n = 7), AD (n = 15), Parkinson's disease and Parkinson's disease dementia (PD/PDD, n = 20) and 15 patients with depression that served as controls (DC) for distinct plasma amyloid-beta (Abeta) peptide patterns. For the analysis of plasma we used immunoprecipitation followed by the quantitative Abeta-SDS-PAGE/immunoblot. For comparison, CSF tau and Abeta1-42 analyses were performed. The major outcome was an increase in Abeta1-40 in plasma of VAD paralleled by a decrease in the ratio of Abeta1-38/Abeta1-40. The ratio Abeta1-38/Abeta1-40 in plasma enabled contrasts of beyond 85% and 80% for discriminating VAD from DC and all other patients, respectively. In CSF, we confirmed the typical CSF biomarker constellation of increased tau and diminished Abeta1-42 levels for AD. The diagnostic accuracy of plasma Abeta1-38/Abeta1-40 for VAD resembled the accuracy of CSF biomarkers for AD. From the presented results, we consider the ratio of plasma Abeta1-38/Abeta1-40 peptides to be a blood-based biomarker candidate for VAD.

Bibl M, Mollenhauer B, Lewczuk P, Esselmann H, Wolf S, Trenkwalder C, Otto M, Stiens G, Rüther E, Kornhuber J, Wiltfang J. · Department of Psychiatry, University of Goettingen, Goettingen, Germany. · Mol Psychiatry. · Pubmed #17339876 No free full text.

Abstract: Biomarkers for differential diagnosis of the three most frequent degenerative forms of dementia, Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementias (FTD), are currently under intensive investigation, but disease-specific biomarkers for FTD and DLB are still lacking. We analyzed 303 cerebrospinal fluid (CSF) samples of 71 AD, 32 DLB and 36 FTD patients in comparison to 93 various other dementias (OD), 20 peripheral neurologic disease (PND) controls, 25 neurodegenerative disorders without dementia (ND) and 26 depressive cognitive complainers (DCC) for distinct CSF amyloid-beta (Abeta) peptide patterns, using the quantitative Abeta-SDS-PAGE/immunoblot. Additionally, the novel electrochemiluminescence technique (MSD) was used to validate the measures on Abeta1-38. The main outcome measures were a striking decrease of Abeta1-42 in AD (P=7.4 x 10(-19)), and most interestingly a pronounced decrease of Abeta1-38 in FTD (P=9.6 x 10(-7)). Moreover, a novel peptide that most probably represents an oxidized alpha-helical form of Abeta1-40 (Abeta1-40(ox)) displayed a highly significant increase in DLB (P=3.7 x 10(-3)) as compared to non-demented disease controls. The overall diagnostic accuracy of percentage Abeta peptide abundances (Abeta1-X%) was clearly superior to absolute CSF Abeta levels. Abeta1-42% and Abeta1-38% enabled contrasts of 85% or beyond to distinguish AD and FTD, respectively, from all other investigated subjects. Abeta1-40(ox)% yielded a diagnostic sensitivity and specificity of 88 and 73% for the detection of DLB among all other investigated patients. We found a strong correlation between Abeta1-38 levels as measured by the Abeta-SDS-PAGE/immunoblot and MSD, respectively. CSF Abeta peptides may reflect disease-specific impact of distinct neurodegenerative processes on Abeta peptide metabolism and represent a potential diagnostic biomarker for AD, FTD and DLB.

Henkel AW, Dittrich PS, Groemer TW, Lemke EA, Klingauf J, Klafki HW, Lewczuk P, Esselmann H, Schwille P, Kornhuber J, Wiltfang J. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · Mol Psychiatry. · Pubmed #17279093 No free full text.

Abstract: The diagnostic potential of large A beta-peptide binding particles (LAPs) in the cerebrospinal fluid (CSF) of Alzheimer's dementia (AD) patients and non-AD controls (nAD) was evaluated. LAPs were detected by confocal spectroscopy in both groups with high inter-individual variation in number. Molecular imaging by confocal microscopy revealed that LAPs are heterogeneous superaggregates that could be subdivided morphologically into four main types (LAP 1-4). LAP-4 type, resembling a 'large chain of pearls', was detected in 42.1% of all nAD controls but it was virtually absent in AD patients. LAP-4 type could be selectively removed by protein A beads, a clear indication that it contained immunoglobulins in addition to beta-amyloid peptides (A beta 1-42). We observed a close correlation between LAPs and immunoglobulin G (IgG) concentration in CSF in controls but not in AD patients. Double labeling of LAPs with anti-A beta and anti-IgG antibodies confirmed that LAP-4 type consisted of A beta and IgG aggregates. Our results assign a central role to the immune system in regulating A beta1-42 homeostasis by clustering this peptide in immunocomplexes.

Wiltfang J, Esselmann H, Bibl M, Hüll M, Hampel H, Kessler H, Frölich L, Schröder J, Peters O, Jessen F, Luckhaus C, Perneczky R, Jahn H, Fiszer M, Maler JM, Zimmermann R, Bruckmoser R, Kornhuber J, Lewczuk P. · Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany. · J Neurochem. · Pubmed #17254013 No free full text.

Abstract: 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 beta peptides ending at the amino acid position of 42 (A beta x-42 and A beta 1-42) are widely accepted biomarkers of Alzheimer's disease (AD). However, in subjects with constitutively high- or low-CSF concentrations of total A beta peptides (tA beta), the NDD interpretation might lead to erroneous conclusions as these biomarkers seem to correlate better with the total A beta 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 A beta x-40 concentrations and decreased A beta x-42/x-40 concentration ratio compared with the group of subjects with low CSF A beta x-40 and normal A beta ratio (p<0.001 in both cases). Furthermore, we observed significantly decreased A beta ratio (p<0.01) in the group of subjects with APOE epsilon 4 allele compared with the group of subjects without this allele. Surprisingly, patients with low-A beta x-40 and the decreased A beta ratio characterized with decreased pTau181 (p<0.05), and unaltered total Tau compared with the subjects with high A beta x-40 and the A beta ratio in the normal range. We conclude that the amyloid beta concentration ratio should replace the 'raw' concentrations of corresponding A beta peptides to improve reliability of the neurochemical dementia diagnosis.

Bibl M, Mollenhauer B, Wolf S, Esselmann H, Lewczuk P, Kornhuber J, Wiltfang J. · Department of Psychiatry, University of Goettingen, Goettingen, Germany. · J Neural Transm. · Pubmed #17245538 No free full text.

Abstract: Cerebrospinal fluid (CSF) carboxyterminally truncated amyloid-beta (Abeta) peptides, Abeta1-42 and tau protein were evaluated in 30 patients with frontotemporal lobe degenerations (FTLD), 30 Alzheimer's disease (AD) patients and 30 non-demented disease controls (NDC) by Abeta-SDS-PAGE/immunoblot as well as commercial ELISAs for Abeta1-42 and total tau. FTLD displayed a significant drop of Abeta1-37 (p = 2.7 x 10(-4)), Abeta1-38 (p = 4.2 x 10(-5)) and Abeta1-42 (p = 3.3 x 10(-4)). Abeta1-42 was selectively decreased in AD (p = 8.5 x 10(-10)). Decreased Abeta1-38 enabled contrasts of beyond 85% to distinguish FTLD from AD and NDC patients, alone or in combination. Accordingly, low CSF Abeta1-37 and Abeta1-38 represent a biomarker candidate for FTLD and may reflect disease-specific changes of APP metabolism. Further validation should be carried out on dementias other than AD, diagnostically relevant control groups without dementia and without any evident affection of the central nervous system and subgroups of FTLD. Moreover, independent methods of measurement should be applied to CSF Abeta1-38.