Johannes Kornhuber - Academia.edu (original) (raw)
Papers by Johannes Kornhuber
JAMA, Jan 19, 2015
Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting... more Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to ...
Journal of Alzheimer's disease : JAD, 2009
Disturbed homocysteine metabolism is a risk factor for Alzheimer's disease (AD) and may contr... more Disturbed homocysteine metabolism is a risk factor for Alzheimer's disease (AD) and may contribute to the disease pathophysiology by increasing both amyloid-beta (Abeta) production and phosphorylated tau (P-tau) accumulation. Here, we evaluated the relationship between the cerebrospinal fluid (CSF) concentrations of homocysteine (Hcys), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and 5-methyltetrahydrofolate (5-MTHF), and the markers for AD pathology, Abeta(1-42) and P-tau181, in 98 cognitively healthy subjects aged 16-81 years and 54 AD patients. In multivariate regression tests including age, gender, creatinine, and presence of the apolipoprotein E epsilon4 allele, P-tau181 was associated with SAH (beta = 0.490; p < 0.001), 5-MTHF (beta = -0.273; p = 0.010) levels, and SAM/SAH ratio (beta = -0.319; p = 0.013) in controls, and with SAH (beta = 0.529; p = 0.001) in AD patients. The levels of Abeta(1-42) were not associated with the CSF concentrations of Hcys, SA...
Journal of Alzheimer's disease : JAD, 2015
The increasing role of cerebrospinal fluid (CSF) biomarkers in the early diagnosis of Alzheimer&#... more The increasing role of cerebrospinal fluid (CSF) biomarkers in the early diagnosis of Alzheimer's disease (AD) is reflected in recently published diagnostic and/or research criteria. A growing body of evidence suggests better diagnostic performance of the amyloid-β (Aβ)42/40 CSF concentration ratio compared to the Aβ42 concentration alone. (a) to analytically validate two novel ELISAs capable to measure Aβ1-40 and Aβ1-42 in the CSF, and (b) to compare the diagnostic accuracies of Aβ1-42 and Aβ42/40 ratio. In this study, (a) the novel Aβ1-40 and Aβ1-42 ELISAs (IBL International GmbH, Hamburg, Germany) have been analytically validated, and (b) a clinical study has been performed comparing the diagnostic performance of the CSF Aβ42/40 concentration ratio and the CSF Aβ42 concentration. In the analytical part of the study, only marginal cross-reactivity (Aβ1-42 versus Aβ1-40) was observed; recoveries were in the range of 85-100% for the samples diluted 1 : 20-1 : 640 (Aβ1-40), and 9...
Journal of Alzheimer's disease : JAD, 2014
Little information is available on the rostro-caudal concentration gradient of Alzheimer's di... more Little information is available on the rostro-caudal concentration gradient of Alzheimer's disease (AD) biomarkers. We studied the concentrations of amyloid-β (Aβ) peptides 1-42 and 1-40 as well as the Tau and pTau proteins in simultaneously collected ventricular and lumbar cerebrospinal fluid (CSF) samples. The samples were simultaneously collected from the ventricle and the lumbar spinal canal in two groups of patients: 10 subjects being treated for normal pressure hydrocephalus (NPH) by the placement of a ventriculo-peritoneal shunt and 5 patients treated simultaneously with an external ventricular drain and a lumbar CSF drain due to posttraumatic hydrocephalus (PTH). The ventricular-lumbar (V/L) concentration ratio for Aβ1-40 was 0.81 in NPH patients and 0.71 in PTH patients. The V/L-ratio for Aβ1-42 was 0.84 in NPH, reflecting significantly higher concentrations in lumbar CSF than in ventricular CSF, and 1.02 in PTH patients. The V/L-ratios for Tau and pTau differed signifi...
Journal of Alzheimer's disease : JAD, 2014
Changes in the concentrations of amyloid-β (Aβ) in the body fluids are the earliest alterations o... more Changes in the concentrations of amyloid-β (Aβ) in the body fluids are the earliest alterations observed in Alzheimer's disease (AD), however, there is a lack of data about how early these alterations occur, before the onset of the clinical symptoms. APOE genotype is the most recognized genetic risk/protective factor of AD, meaning that a group of non-demented persons carrying ε4 allele is enriched in the subjects who will develop AD, compared to the group of non-carriers. Therefore, we studied the plasma concentrations of Aβ peptides (Aβ1-42, Aβ1-40, Aβx-42, and Aβx-40), and the APOE genotype in 173 young volunteers (average age, 28 ± 7.6 years) without memory deficits, in order to see whether the non-demented group of subjects at risk already characterize with Aβ changes three-to-four decades before the age at which dementia usually occurs. We did not find statistically significant differences among the groups of ε4 carriers, ε3 homozygotes, and ε2 carriers. We conclude that t...
Journal of Alzheimer's disease : JAD, 2012
In this report, we confirm our previous findings of increased concentrations of soluble amyloid-β... more In this report, we confirm our previous findings of increased concentrations of soluble amyloid-β protein precursor (sAβPP) in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large cohort of patients (n = 314), not overlapping with those of our previous study, and we extend our observations by including a control group of participants with normal cognition. In addition, we investigate the effects of age, the APOEε4 genotype, and the blood-CSF barrier function on the concentrations of sAβPPα and sAβPPβ. The study participants were categorized according to clinical-neuropsychological criteria, supported by CSF neurochemical dementia diagnostics (NDD) analyses. sAβPPα concentrations in the AD group (132.0 ± 44.8) were significantly higher than in the control group (105.3 ± 37.3, p < 0.0005) but did not differ from the MCI-AD group (138.5 ± 39.5, p = 0.91). The MCI-AD group differed significantly from the MCI-O (97.3 ± ...
Journal of Alzheimer's disease : JAD, 2010
In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the cl... more In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the clinical manifestation of the disease. Biomarkers for AD, such as the cerebrospinal fluid (CSF) concentrations of amyloid-β1-42 (Aβ1-42) and tau phosphorylated at threonine 181 (pTau181), may reflect these cerebral changes relatively early. Accordingly, cognitively healthy subjects at risk for AD often have altered CSF concentrations of Aβ1-42 and pTau181. In this study, we assessed the effects and interaction of two strong risk factors for AD, aging and the presence of the APOEε4 allele, on the CSF Aβ1-42 and pTau181 concentrations in 280 adults with normal cognition across the lifespan. For comparison, we further included 152 patients with probable AD. We found significant effects of age on the CSF Aβ1-42 and pTau181, and of the APOEε4 genotype on the Aβ1-42 levels in the cognitively normal participants. Carrying the APOEε4 allele was associated with a significant decrease of the Aβ1-42 ...
Biological psychiatry, 2004
The advent of new therapeutic avenues for Alzheimer's disease (AD) calls for an improved earl... more The advent of new therapeutic avenues for Alzheimer's disease (AD) calls for an improved early and differential diagnosis. 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. 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). Th...
American Journal of Psychiatry, 1999
After discontinuation of neuroleptic drugs, their antipsychotic and antiparkinsonian effects are ... more After discontinuation of neuroleptic drugs, their antipsychotic and antiparkinsonian effects are still present for a prolonged period. It is not known whether the extended effects of neuroleptic drugs in humans are due to the continued presence of drug in brain tissue or to long-lasting drug-induced physiologic changes. The aim of this study was to directly examine haloperidol concentrations in human brain tissue in relation to drug-free time. Method: Haloperidol concentrations were measured in five regions (temporal cortex, cingulate gyrus, caudate nucleus, dentate nucleus, corpus callosum) of the postmortem brains of 11 patients previously treated with haloperidol. Haloperidol was analyzed by means of high-performance liquid chromatography with ultraviolet detection. The half-life in brain tissue was estimated by a population kinetic analysis. Results: Haloperidol concentrations in the human brain tissue were 10-30 times higher than optimal serum concentrations used in the treatment of schizophrenia. Haloperidol concentrations appeared to be homogeneously distributed across different brain areas within a single patient. There was no apparent relation between duration of treatment and mean haloperidol concentration. Higher doses of haloperidol seemed to be related to higher concentrations in brain tissue. The elimination half-life from brain tissue was calculated to be 6.8 days. Conclusions: The results may have implications for clinical treatment decisions and the design of clinical research protocols. Patients exposed to haloperidol cannot be considered to be free of residual effects of the drug for a number of weeks after withdrawal. (Am J Psychiatry 1999; 156:885-890) METHOD Brain tissue was taken at autopsy from 11 subjects who had been treated with oral doses of haloperidol. The brains were collected between 1989
The Journal of Nutrition Health and Aging, 2008
Background : Alzheimer&amp;amp;amp;amp;amp;amp;amp;#x27;s disease (AD) is a devastating n... more Background : Alzheimer&amp;amp;amp;amp;amp;amp;amp;#x27;s disease (AD) is a devastating neurodegenerative affection that is approaching epidemic proportions in the industrialized world due to aging of the populations. Recently, new revisited AD diagnosis criteria point out the major interest of CSF biomarkers. The dosage ...
Alzheimer's Research & Therapy, 2015
Introduction: White matter (WM) magnetic resonance imaging (MRI) hyperintensities are common in A... more Introduction: White matter (WM) magnetic resonance imaging (MRI) hyperintensities are common in Alzheimer's disease (AD), but their pathophysiological relevance and relationship to genetic factors are unclear. In the present study, we investigated potential apolipoprotein E (APOE)-dependent effects on the extent and cognitive impact of WM hyperintensities in patients with AD.
Rapid Communications in Mass Spectrometry, 2003
The patterns of amyloid β (Aβ) peptides in human cerebrospinal fluid (CSF) and brain homogenates ... more The patterns of amyloid β (Aβ) peptides in human cerebrospinal fluid (CSF) and brain homogenates were studied by surface‐enhanced laser desorption/ionization (SELDI) time‐of‐flight (TOF) mass spectrometry, and the results were compared with those obtained by Aβ‐SDS‐PAGE/immunoblot. Apart from the peptides known in the literature to occur in the CSF, we postulate the existence of a novel, previously not described peptide, either Aβ1–45 or Aβ2–46. This peptide was observed exclusively in a pool of samples originating from patients with AD, i.e. CSF and postmortem brain homogenates, but not in either the pooled CSF samples nor the pooled brain homogenates of the non‐demented controls. Similarly to our previous results, Aβ1–42 was decreased in the CSF in AD. Expectedly, brain homogenates of the control subjects did not show the presence of Aβ peptides. Compared with Aβ‐SDS‐PAGE/immunoblot, SELDI‐TOF enabled more precise analysis of Aβ peptides in the human material. We conclude that SELDI‐TOF offers a promising tool for dementia expression pattern profiling using a minute amount of a biological sample. Copyright © 2003 John Wiley & Sons, Ltd.
Brain : a journal of neurology, Jan 17, 2015
Three sets of research criteria are available for diagnosis of Alzheimer's disease in subject... more Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing...
Der vorliegende Bericht beschreibt ein vom Bundesministerium für Gesundheit gefördertes Vorhaben ... more Der vorliegende Bericht beschreibt ein vom Bundesministerium für Gesundheit gefördertes Vorhaben zum «Leuchtturmprojekt Demenz» im Themenfeld 1 «Therapie und Pflegemaßnahmen: Wirksamkeit unter Alltagsbedingungen». Hierbei handelt es sich um eine multizentrische randomisierte Interventionsstudie, die den Einfluss von Sport (multimodale sportliche Aktivität) unter kontrollierten Bedingungen auf die kognitive Entwicklung von Alzheimer-Patienten im frühen Stadium prüft. In einem zweiarmigen Design werden je 150 Patienten mit früher AD unter Verum- bzw. Kontroll-Bedingungen untersucht. Die Verum-Gruppe erhält ein spezifisches sportliches Trainingsprogramm. In der Kontrollgruppe werden lediglich Dehnungsübungen durchgeführt. Primäre Endpunkte der Studie sind die kognitive Leistung der Patienten sowie deren Alltagskompetenz im Verlauf. Die gesundheitsbezogene Lebensqualität der Patienten sowie etwaige Verhaltensstörungen und depressive Symptome werden als sekundäre Endpunkte erfasst. Darüber hinaus werden die Angehörigen zur krankheitsbezogenen Belastung befragt und auf depressive Symptome untersucht. Angelehnt an die Hypothesen der «Initiative Demenzversorgung in der Allgemeinmedizin» (IDA) sollen entsprechende nicht-medikamentöse Versorgungsangebote dazu beitragen, dass Patienten länger in ihrem gewohnten häuslichen Umfeld leben. Im Sinne der Nachhaltigkeit der zu erwartenden Ergebnisse wird ein «Do it yourself»-Manual erstellt, mit dem das Trainingsprogramm auch ohne professionelle Anleitung, z. B. im Rahmen von Selbsthilfegruppen durchgeführt werden kann. Die weitere Implementierung (z. B. in Internetforen und weiteren Medien) wird durch einen Beirat der lokalen Krankenkassen, Gesundheitsämter und der Deutschen Alzheimer-Gesellschaft unterstützt.
Neurobiology of aging, 2015
Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer&#... more Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's 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 ...
Neurology, Jan 25, 2015
To test whether, in individuals with mild cognitive impairment (MCI), different measures of subje... more To test whether, in individuals with mild cognitive impairment (MCI), different measures of subjective cognitive decline (SCD) in the memory domain predict abnormal CSF biomarkers of Alzheimer disease (AD). We analyzed the multicenter baseline (cross-sectional) data of 245 patients with MCI. SCD was measured quantitatively with the Subjective Memory Decline Scale (SMDS) and qualitatively by assessing particular concerns associated with self-experienced worsening of memory. Logistic regression models were used to examine associations between SCD and abnormal CSF biomarkers, taking into account objective memory impairment, depressive symptoms, and education as covariates. Abnormal CSF β-amyloid 1-42 (Aβ42) and more depressive symptoms were associated with higher SMDS scores and with the report of memory concerns. Risk of abnormal CSF Aβ42 increased by an estimated 57% for a 1-SD increase in SMDS scores and was doubled in patients who had SMDS scores >4 or who reported memory concer...
This paper focuses on psychiatric aspects of portal-systemic encephalopathy (PSE) due to chronic ... more This paper focuses on psychiatric aspects of portal-systemic encephalopathy (PSE) due to chronic liver disease and/or portal-systemic shunting. Clinical syndromes of PSE are discussed from the point of view of biological psychiatry, but, psychological consequences of concomitant cognitive disorders are also addressed. Psychiatric symptoms of early PSE and sleep disorders in patients with chronic liver disease are of specific interest.
JAMA, Jan 19, 2015
Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting... more Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to ...
Journal of Alzheimer's disease : JAD, 2009
Disturbed homocysteine metabolism is a risk factor for Alzheimer's disease (AD) and may contr... more Disturbed homocysteine metabolism is a risk factor for Alzheimer's disease (AD) and may contribute to the disease pathophysiology by increasing both amyloid-beta (Abeta) production and phosphorylated tau (P-tau) accumulation. Here, we evaluated the relationship between the cerebrospinal fluid (CSF) concentrations of homocysteine (Hcys), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and 5-methyltetrahydrofolate (5-MTHF), and the markers for AD pathology, Abeta(1-42) and P-tau181, in 98 cognitively healthy subjects aged 16-81 years and 54 AD patients. In multivariate regression tests including age, gender, creatinine, and presence of the apolipoprotein E epsilon4 allele, P-tau181 was associated with SAH (beta = 0.490; p < 0.001), 5-MTHF (beta = -0.273; p = 0.010) levels, and SAM/SAH ratio (beta = -0.319; p = 0.013) in controls, and with SAH (beta = 0.529; p = 0.001) in AD patients. The levels of Abeta(1-42) were not associated with the CSF concentrations of Hcys, SA...
Journal of Alzheimer's disease : JAD, 2015
The increasing role of cerebrospinal fluid (CSF) biomarkers in the early diagnosis of Alzheimer&#... more The increasing role of cerebrospinal fluid (CSF) biomarkers in the early diagnosis of Alzheimer's disease (AD) is reflected in recently published diagnostic and/or research criteria. A growing body of evidence suggests better diagnostic performance of the amyloid-β (Aβ)42/40 CSF concentration ratio compared to the Aβ42 concentration alone. (a) to analytically validate two novel ELISAs capable to measure Aβ1-40 and Aβ1-42 in the CSF, and (b) to compare the diagnostic accuracies of Aβ1-42 and Aβ42/40 ratio. In this study, (a) the novel Aβ1-40 and Aβ1-42 ELISAs (IBL International GmbH, Hamburg, Germany) have been analytically validated, and (b) a clinical study has been performed comparing the diagnostic performance of the CSF Aβ42/40 concentration ratio and the CSF Aβ42 concentration. In the analytical part of the study, only marginal cross-reactivity (Aβ1-42 versus Aβ1-40) was observed; recoveries were in the range of 85-100% for the samples diluted 1 : 20-1 : 640 (Aβ1-40), and 9...
Journal of Alzheimer's disease : JAD, 2014
Little information is available on the rostro-caudal concentration gradient of Alzheimer's di... more Little information is available on the rostro-caudal concentration gradient of Alzheimer's disease (AD) biomarkers. We studied the concentrations of amyloid-β (Aβ) peptides 1-42 and 1-40 as well as the Tau and pTau proteins in simultaneously collected ventricular and lumbar cerebrospinal fluid (CSF) samples. The samples were simultaneously collected from the ventricle and the lumbar spinal canal in two groups of patients: 10 subjects being treated for normal pressure hydrocephalus (NPH) by the placement of a ventriculo-peritoneal shunt and 5 patients treated simultaneously with an external ventricular drain and a lumbar CSF drain due to posttraumatic hydrocephalus (PTH). The ventricular-lumbar (V/L) concentration ratio for Aβ1-40 was 0.81 in NPH patients and 0.71 in PTH patients. The V/L-ratio for Aβ1-42 was 0.84 in NPH, reflecting significantly higher concentrations in lumbar CSF than in ventricular CSF, and 1.02 in PTH patients. The V/L-ratios for Tau and pTau differed signifi...
Journal of Alzheimer's disease : JAD, 2014
Changes in the concentrations of amyloid-β (Aβ) in the body fluids are the earliest alterations o... more Changes in the concentrations of amyloid-β (Aβ) in the body fluids are the earliest alterations observed in Alzheimer's disease (AD), however, there is a lack of data about how early these alterations occur, before the onset of the clinical symptoms. APOE genotype is the most recognized genetic risk/protective factor of AD, meaning that a group of non-demented persons carrying ε4 allele is enriched in the subjects who will develop AD, compared to the group of non-carriers. Therefore, we studied the plasma concentrations of Aβ peptides (Aβ1-42, Aβ1-40, Aβx-42, and Aβx-40), and the APOE genotype in 173 young volunteers (average age, 28 ± 7.6 years) without memory deficits, in order to see whether the non-demented group of subjects at risk already characterize with Aβ changes three-to-four decades before the age at which dementia usually occurs. We did not find statistically significant differences among the groups of ε4 carriers, ε3 homozygotes, and ε2 carriers. We conclude that t...
Journal of Alzheimer's disease : JAD, 2012
In this report, we confirm our previous findings of increased concentrations of soluble amyloid-β... more In this report, we confirm our previous findings of increased concentrations of soluble amyloid-β protein precursor (sAβPP) in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large cohort of patients (n = 314), not overlapping with those of our previous study, and we extend our observations by including a control group of participants with normal cognition. In addition, we investigate the effects of age, the APOEε4 genotype, and the blood-CSF barrier function on the concentrations of sAβPPα and sAβPPβ. The study participants were categorized according to clinical-neuropsychological criteria, supported by CSF neurochemical dementia diagnostics (NDD) analyses. sAβPPα concentrations in the AD group (132.0 ± 44.8) were significantly higher than in the control group (105.3 ± 37.3, p < 0.0005) but did not differ from the MCI-AD group (138.5 ± 39.5, p = 0.91). The MCI-AD group differed significantly from the MCI-O (97.3 ± ...
Journal of Alzheimer's disease : JAD, 2010
In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the cl... more In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the clinical manifestation of the disease. Biomarkers for AD, such as the cerebrospinal fluid (CSF) concentrations of amyloid-β1-42 (Aβ1-42) and tau phosphorylated at threonine 181 (pTau181), may reflect these cerebral changes relatively early. Accordingly, cognitively healthy subjects at risk for AD often have altered CSF concentrations of Aβ1-42 and pTau181. In this study, we assessed the effects and interaction of two strong risk factors for AD, aging and the presence of the APOEε4 allele, on the CSF Aβ1-42 and pTau181 concentrations in 280 adults with normal cognition across the lifespan. For comparison, we further included 152 patients with probable AD. We found significant effects of age on the CSF Aβ1-42 and pTau181, and of the APOEε4 genotype on the Aβ1-42 levels in the cognitively normal participants. Carrying the APOEε4 allele was associated with a significant decrease of the Aβ1-42 ...
Biological psychiatry, 2004
The advent of new therapeutic avenues for Alzheimer's disease (AD) calls for an improved earl... more The advent of new therapeutic avenues for Alzheimer's disease (AD) calls for an improved early and differential diagnosis. 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. 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). Th...
American Journal of Psychiatry, 1999
After discontinuation of neuroleptic drugs, their antipsychotic and antiparkinsonian effects are ... more After discontinuation of neuroleptic drugs, their antipsychotic and antiparkinsonian effects are still present for a prolonged period. It is not known whether the extended effects of neuroleptic drugs in humans are due to the continued presence of drug in brain tissue or to long-lasting drug-induced physiologic changes. The aim of this study was to directly examine haloperidol concentrations in human brain tissue in relation to drug-free time. Method: Haloperidol concentrations were measured in five regions (temporal cortex, cingulate gyrus, caudate nucleus, dentate nucleus, corpus callosum) of the postmortem brains of 11 patients previously treated with haloperidol. Haloperidol was analyzed by means of high-performance liquid chromatography with ultraviolet detection. The half-life in brain tissue was estimated by a population kinetic analysis. Results: Haloperidol concentrations in the human brain tissue were 10-30 times higher than optimal serum concentrations used in the treatment of schizophrenia. Haloperidol concentrations appeared to be homogeneously distributed across different brain areas within a single patient. There was no apparent relation between duration of treatment and mean haloperidol concentration. Higher doses of haloperidol seemed to be related to higher concentrations in brain tissue. The elimination half-life from brain tissue was calculated to be 6.8 days. Conclusions: The results may have implications for clinical treatment decisions and the design of clinical research protocols. Patients exposed to haloperidol cannot be considered to be free of residual effects of the drug for a number of weeks after withdrawal. (Am J Psychiatry 1999; 156:885-890) METHOD Brain tissue was taken at autopsy from 11 subjects who had been treated with oral doses of haloperidol. The brains were collected between 1989
The Journal of Nutrition Health and Aging, 2008
Background : Alzheimer&amp;amp;amp;amp;amp;amp;amp;#x27;s disease (AD) is a devastating n... more Background : Alzheimer&amp;amp;amp;amp;amp;amp;amp;#x27;s disease (AD) is a devastating neurodegenerative affection that is approaching epidemic proportions in the industrialized world due to aging of the populations. Recently, new revisited AD diagnosis criteria point out the major interest of CSF biomarkers. The dosage ...
Alzheimer's Research & Therapy, 2015
Introduction: White matter (WM) magnetic resonance imaging (MRI) hyperintensities are common in A... more Introduction: White matter (WM) magnetic resonance imaging (MRI) hyperintensities are common in Alzheimer's disease (AD), but their pathophysiological relevance and relationship to genetic factors are unclear. In the present study, we investigated potential apolipoprotein E (APOE)-dependent effects on the extent and cognitive impact of WM hyperintensities in patients with AD.
Rapid Communications in Mass Spectrometry, 2003
The patterns of amyloid β (Aβ) peptides in human cerebrospinal fluid (CSF) and brain homogenates ... more The patterns of amyloid β (Aβ) peptides in human cerebrospinal fluid (CSF) and brain homogenates were studied by surface‐enhanced laser desorption/ionization (SELDI) time‐of‐flight (TOF) mass spectrometry, and the results were compared with those obtained by Aβ‐SDS‐PAGE/immunoblot. Apart from the peptides known in the literature to occur in the CSF, we postulate the existence of a novel, previously not described peptide, either Aβ1–45 or Aβ2–46. This peptide was observed exclusively in a pool of samples originating from patients with AD, i.e. CSF and postmortem brain homogenates, but not in either the pooled CSF samples nor the pooled brain homogenates of the non‐demented controls. Similarly to our previous results, Aβ1–42 was decreased in the CSF in AD. Expectedly, brain homogenates of the control subjects did not show the presence of Aβ peptides. Compared with Aβ‐SDS‐PAGE/immunoblot, SELDI‐TOF enabled more precise analysis of Aβ peptides in the human material. We conclude that SELDI‐TOF offers a promising tool for dementia expression pattern profiling using a minute amount of a biological sample. Copyright © 2003 John Wiley & Sons, Ltd.
Brain : a journal of neurology, Jan 17, 2015
Three sets of research criteria are available for diagnosis of Alzheimer's disease in subject... more Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing...
Der vorliegende Bericht beschreibt ein vom Bundesministerium für Gesundheit gefördertes Vorhaben ... more Der vorliegende Bericht beschreibt ein vom Bundesministerium für Gesundheit gefördertes Vorhaben zum «Leuchtturmprojekt Demenz» im Themenfeld 1 «Therapie und Pflegemaßnahmen: Wirksamkeit unter Alltagsbedingungen». Hierbei handelt es sich um eine multizentrische randomisierte Interventionsstudie, die den Einfluss von Sport (multimodale sportliche Aktivität) unter kontrollierten Bedingungen auf die kognitive Entwicklung von Alzheimer-Patienten im frühen Stadium prüft. In einem zweiarmigen Design werden je 150 Patienten mit früher AD unter Verum- bzw. Kontroll-Bedingungen untersucht. Die Verum-Gruppe erhält ein spezifisches sportliches Trainingsprogramm. In der Kontrollgruppe werden lediglich Dehnungsübungen durchgeführt. Primäre Endpunkte der Studie sind die kognitive Leistung der Patienten sowie deren Alltagskompetenz im Verlauf. Die gesundheitsbezogene Lebensqualität der Patienten sowie etwaige Verhaltensstörungen und depressive Symptome werden als sekundäre Endpunkte erfasst. Darüber hinaus werden die Angehörigen zur krankheitsbezogenen Belastung befragt und auf depressive Symptome untersucht. Angelehnt an die Hypothesen der «Initiative Demenzversorgung in der Allgemeinmedizin» (IDA) sollen entsprechende nicht-medikamentöse Versorgungsangebote dazu beitragen, dass Patienten länger in ihrem gewohnten häuslichen Umfeld leben. Im Sinne der Nachhaltigkeit der zu erwartenden Ergebnisse wird ein «Do it yourself»-Manual erstellt, mit dem das Trainingsprogramm auch ohne professionelle Anleitung, z. B. im Rahmen von Selbsthilfegruppen durchgeführt werden kann. Die weitere Implementierung (z. B. in Internetforen und weiteren Medien) wird durch einen Beirat der lokalen Krankenkassen, Gesundheitsämter und der Deutschen Alzheimer-Gesellschaft unterstützt.
Neurobiology of aging, 2015
Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer&#... more Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's 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 ...
Neurology, Jan 25, 2015
To test whether, in individuals with mild cognitive impairment (MCI), different measures of subje... more To test whether, in individuals with mild cognitive impairment (MCI), different measures of subjective cognitive decline (SCD) in the memory domain predict abnormal CSF biomarkers of Alzheimer disease (AD). We analyzed the multicenter baseline (cross-sectional) data of 245 patients with MCI. SCD was measured quantitatively with the Subjective Memory Decline Scale (SMDS) and qualitatively by assessing particular concerns associated with self-experienced worsening of memory. Logistic regression models were used to examine associations between SCD and abnormal CSF biomarkers, taking into account objective memory impairment, depressive symptoms, and education as covariates. Abnormal CSF β-amyloid 1-42 (Aβ42) and more depressive symptoms were associated with higher SMDS scores and with the report of memory concerns. Risk of abnormal CSF Aβ42 increased by an estimated 57% for a 1-SD increase in SMDS scores and was doubled in patients who had SMDS scores >4 or who reported memory concer...
This paper focuses on psychiatric aspects of portal-systemic encephalopathy (PSE) due to chronic ... more This paper focuses on psychiatric aspects of portal-systemic encephalopathy (PSE) due to chronic liver disease and/or portal-systemic shunting. Clinical syndromes of PSE are discussed from the point of view of biological psychiatry, but, psychological consequences of concomitant cognitive disorders are also addressed. Psychiatric symptoms of early PSE and sleep disorders in patients with chronic liver disease are of specific interest.