Holger Jahn - Academia.edu (original) (raw)

Papers by Holger Jahn

Alzheimers & Dementia, Jul 1, 2015

8 and 18 months and to evaluate whether the antiepileptic drug Levetiracetam have any effect on s... more 8 and 18 months and to evaluate whether the antiepileptic drug Levetiracetam have any effect on spontaneous seizures. Methods: Video-EEG/EMG monitoring over 24-hrs of the light dark cycle was carried out at baseline. At 8 months, network excitability was examined by quantifying susceptibility of pentylenetetrazole (PTZ) (30 mg/kg) to induce seizures. At 18 months, the frequency of epileptiform SWD was repeatedly quantified before and after acute and sub-chronic administration of leviracetam (150 mg/kg). Results: At 8 months, APP/PS1 had no spontaneous seizures across different vigilance states. PTZ provoked seizures at shorter latencies in APP/PS1 mice compared to littermate controls, which were associated with a significant increase in EEG power within 4-30 Hz frequency range. These changes were short lasting and rapidly abolished. At 18 months, 60% of APP/PS1 mice expressed spontaneous non-convulsive seizures (30-40s duration) and epileptiform SWD activity at shorter duration i.e. 0.3 -6.0 s. The observed behavioral correlate included motor arrest accompanied by subtle myoclonic jerks. Conclusions: Consistent with previous reports, aged APP/PS1 mice exhibit high incidence of unprovoked epileptic activity, whereas no such abnormalities were detected at a young age. Follow-up studies are underway to investigate whether acute or sub-chronic Levetiracetam can reduce or prevent this epileptiform activity.

Alzheimers & Dementia, Jul 1, 2015

JAMA Psychiatry

; for the International FTD-Genetics Consortium (IFGC), the German Frontotemporal Lobar Degenerat... more ; for the International FTD-Genetics Consortium (IFGC), the German Frontotemporal Lobar Degeneration (FTLD) Consortium, and the PRONIA Consortium IMPORTANCE The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. OBJECTIVE To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). DESIGN, SETTING, AND PARTICIPANTS This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration.

Journal of Neural Transmission

ApoE4, the strongest genetic risk factor for Alzheimer’s disease (AD), has been shown to be asso... more ApoE4, the strongest genetic risk factor for Alzheimer’s disease (AD), has been shown to be associated with both beta-amyloid (Aβ) and tau pathology, with the strongest evidence for effects on Aβ, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aβ42, total tau (t-tau), phospho-tau181 (p-tau), and with the progression of decline in a large cohort of MCI subjects, both progressors to AD and other dementias, as well as non-progressors. We analyzed associations of CSF Aβ42, p-tau and t-tau with ApoE4 allele frequency cross-sectionally and longitudinally over 3 years of follow-up in 195 individuals with a diagnosis of MCI-stable, MCI-AD converters and MCI progressing to other dementias from the German Dementia Competence Network. In the total sample, ApoE4 carriers had lower concentrations of CSF Aβ42, and increased concentrations of t-tau and p-tau compared to non-carriers in a gene dose...


The miRBase-21 database currently lists 1881 microRNA (miRNA) precursors and 2585 unique mature h... more The miRBase-21 database currently lists 1881 microRNA (miRNA) precursors and 2585 unique mature human miRNAs. Since their discovery, miRNAs have proved to present a new level of epigenetic post-transcriptional control of protein synthesis. Initial results point to a possible involvement of miRNA in Alzheimer’s disease (AD). We applied OpenArray technology to profile the expression of 1178 unique miRNAs in cerebrospinal fluid (CSF) samples of AD patients (n = 22) and controls (n = 28). Using a Cq of 34 as cut-off, we identi-fied positive signals for 441 miRNAs, while 729 miRNAs could not be detected, indicating that at least 37 % of miRNAs are present in the brain. We found 74 miRNAs being down-and 74 miRNAs being up-regulated in AD using a 1.5 fold change threshold. By applying the new explorative “Measure of relevance”method, 6 reliable and 9 informative biomarkers were identified. Confirmatory MANCOVA revealed reliablemiR-100, miR-146a and miR-1274a as differentially expressed in ...

Dialogues in Clinical Neuroscience, 2013

Loss of memory is among the first symptoms reported by patients suffering from…

Neurology, Jan 9, 2018

To determine the association of serum neurofilament light chain (NfL) with functional deteriorati... more To determine the association of serum neurofilament light chain (NfL) with functional deterioration and brain atrophy during follow-up of patients with behavioral variant frontotemporal dementia (bvFTD). Blood NfL levels from 74 patients with bvFTD, 26 with Alzheimer disease (AD), 17 with mild cognitive impairment (MCI), and 15 healthy controls (Con) at baseline and follow-up were determined and analyzed for the diagnostic potential in relation to functional assessment (Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB], frontotemporal lobar degeneration-related CDR-SOB, Mini-Mental State Examination [MMSE]) and brain volumetry. At baseline, serum NfL level correlated with CSF NfL (bvFTD = 0.706, < 0.0001; AD/MCI = 0.666, = 0.0003). Highest serum levels were observed in bvFTD ( <0 0.0001 vs Con and MCI, = 0.0078 vs AD, respectively). Discrimination of bvFTD from Con/MCI/AD was possible with 91%/74%/74% sensitivity and 79%/74%/58% specificity. At follow-up, serum NfL increas...

Alzheimer's research & therapy, Jan 25, 2018

With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), inst... more With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), instruments for the follow-up of patients are needed to describe disease progression and to evaluate potential therapeutic effects. So far, volumetric brain changes have been proposed as clinical endpoints in the literature, but cognitive scores are still lacking. This study followed disease progression predominantly in language-based performance within 1 year and defined a PPA sum score which can be used in therapeutic interventions. We assessed 28 patients with nonfluent variant PPA, 17 with semantic variant PPA, 13 with logopenic variant PPA, and 28 healthy controls in detail for 1 year. The most informative neuropsychological assessments were combined to a sum score, and associations between brain atrophy were investigated followed by a sample size calculation for clinical trials. Significant absolute changes up to 20% in cognitive tests were found after 1 year. Semantic and phonemic wor...

PloS one, 2018

Information on circulating miRNAs in frontotemporal lobar degeneration is very limited and confli... more Information on circulating miRNAs in frontotemporal lobar degeneration is very limited and conflicting results have complicated an interpretation in Alzheimer's disease thus far. In the present study we I) collected samples from multiple clinical centers across Germany, II) defined 3 homogenous patient groups with high sample sizes (bvFTD n = 48, AD n = 48 and cognitively healthy controls n = 44), III) compared expression levels in both CSF and serum samples and IV) detected a limited set of miRNAs by using a MIQE compliant protocol based on SYBR-green miRCURY assays that have proven reliable to generate reproducible results. We included several quality controls that identified and reduced technical variation to increase the reliability of our data. We showed that the expression levels of circulating miRNAs measured in CSF did not correlate with levels in serum. Using cluster analysis we found expression pattern in serum that, in part, reflects the genomic organization and affil...

Frontiers in aging neuroscience, 2018

The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosi... more The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to mutation carriers. This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls. Atlas-based volumetry was performed in 13 affected FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status. Compared to sporadic patients, mutation...

Journal of neurology, neurosurgery, and psychiatry, Jan 15, 2017

Neurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mech... more Neurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mechanisms might help in diagnosis, staging and prediction of outcome. We aimed at determining the origin and differential diagnostic and prognostic potential of the putative marker of microglial activation chitotriosidase (CHIT1). Altogether 316 patients were included, comprising patients with sporadic ALS, ALS mimics (disease controls (DCo)), frontotemporal lobar degeneration (FTLD), Creutzfeldt-Jakob disease (CJD), Alzheimer's disease (AD), Parkinson's disease (PD) and healthy controls (Con). CHIT1 and neurofilament levels were determined in cerebrospinal fluid (CSF) and blood and analysed with regard to diagnostic sensitivity and specificity and prognostic performance. Additionally, postmortem tissue was analysed for CHIT1 expression. In ALS, CHIT1 CSF levels were higher compared with Con (p<0.0001), DCo (p<0.05) and neurodegenerative diseases (AD p<0.05, PD p<0.01, F...

Sleep, 2003

Study Objectives: Besides regulating hormone secretion, steroids also modulate sleep architecture... more Study Objectives: Besides regulating hormone secretion, steroids also modulate sleep architecture in specific ways. To simulate a state of altered glucocorticoid-and mineralocorticoid-receptor occupation, we administered metyrapone, an 11-β-hydroxylase inhibitor, that blocks adrenal cortisol synthesis and inhibits the 11-β-hydroxysteroiddehydrogenase type-1 enzyme in the central nervous system and investigated endocrine changes and the sleep electroencephalogram. Design: Each volunteer spent 4 nights in the sleep laboratory, the first of which served to habituate the subject to the conditions in the laboratory. The volunteers underwent 3 trial conditions in random order and in a single-blind design receiving 2 doses of metyrapone (4.5 g or 6.0 g) or placebo on the day before the sleep electroencephalogram recordings. Setting: Sleep laboratory. Participants: 8 healthy male volunteers. Measurements and Results: The corticotropin secretion was significantly enhanced by metyrapone, while the cortisol secretion remained largely unchanged. Growth hormone, progesterone, and dehydroepiandros-terone concentrations were also significantly increased by both doses. Metyrapone induced a pronounced reduction in slow-wave sleep and had slight but nonlinear effects upon rapid eye movement sleep. Parameters of sleep quality were not different between groups. Conclusions: Metyrapone induces pronounced effects on hormonal secretion and the sleep electroencephalogram. These results are in part comparable to those from experiments with the administration of corticotropin-releasing hormone and with experiments that deplete mineralocorticoid receptors. The findings may be explained by altered steroid synthesis proximal to the enzyme block. Metyrapone exerts not only effects upon adrenocortical steroid synthesis, but also important extra-adrenal effects on central corticosteroid metabolism.

Journal of Neuropathology & Experimental Neurology, 2016

The mechanisms leading to amyloid-b (Ab) accumulation in sporadic Alzheimer disease (AD) are unkn... more The mechanisms leading to amyloid-b (Ab) accumulation in sporadic Alzheimer disease (AD) are unknown but both increased production or impaired clearance likely contribute to aggregation. To understand the potential roles of the extracellular matrix proteoglycan Testican-1 in the pathophysiology of AD, we used samples from AD patients and controls and an in vitro approach. Protein expression analysis showed increased levels of Testican-1 in frontal and temporal cortex of AD patients; histological analysis showed that Testican-1 accumulates and co-aggregates with Ab plaques in the frontal, temporal and entorhinal cortices of AD patients. Proteomic analysis identified 10 fragments of Testican-1 in cerebrospinal fluid (CSF) from AD patients. HEK293T cells expressing human wild type or mutant Ab precursor protein (APP) were transfected with Testican-1. The co-expression of both proteins modified the sorting of Testican-1 into the endocytic pathway leading to its transient accumulation in Golgi, which seemed to affect APP processing, as indicated by reduced Ab40 and Ab42 levels in APP mutant cells. In conclusion, patient data reflect a clearance impairment that may favor Ab accumulation in AD brains and our in vitro model supports the notion that the interaction between APP and Testican-1 may be a key step in the production and aggregation of Ab species.

Journal of Alzheimer's disease : JAD, Jan 17, 2015

The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a... more The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials. To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. In patients with MCI, δ based on a broad range of cognitive scales (including the...

Alzheimer's & Dementia, 2014

Background: Research in older adults with subjective cognitive decline (SCD) has mainly focused o... more Background: Research in older adults with subjective cognitive decline (SCD) has mainly focused on Alzheimer's disease (AD)-related MRI markers, such as hippocampal volume. However, small vessel disease (SVD) is currently established as serious comorbidity in dementia and its preliminary stages. It is therefore important to examine SVD markers in addition to AD markers in older adults presenting with SCD. Objective: The aim of our study was to elucidate the role of SVD markers in late middle-aged to older adults with and without SCD in addition to the commonly found role of AD markers (hippocampal volume). Methods: 67 healthy late middle-aged to older adults participated in this study (mean age 68 years); 25 participants with SCD and 42 participants without SCD. We evaluated quantitative as well as qualitative AD markers (i.e., hippocampal volume and medial temporal lobe atrophy (MTA) scale) and SVD markers (i.e., white matter hyperintensities (WMH) volume, Fazekas scale, microbleeds, and lacunar infarcts), and neuropsychological function and amount of memory complaints. Results: We found a significant effect of SCD on hippocampal atrophy, as assessed using the MTA scale, but not on hippocampal volume. In addition, we found a significant effect of SCD, and amount of memory complaints, on WMH volume and Fazekas score, suggesting larger WMH volumes in participants with SCD. Conclusion: SVD MRI markers are related to amount of memory complaints, in addition to the commonly observed AD MRI markers, as demonstrated by the greater WMHs in healthy late middle-aged to older adults with SCD.

Neurochemical Research, 1999

Prothrombin, known to be expressed in brain and to possess growth modulating properties, has been... more Prothrombin, known to be expressed in brain and to possess growth modulating properties, has been suggested to be involved in the pathogenesis of Alzheimer's disease (AD). We studied prothrombin concentration in lumbar CSF (L-CSF) in patients with AD (n = 25), neurologic disease controls (NDC; n = 33) covering a wide range of neurologic disorders, and subjects with Guillain-Barre syndrome (GBS; n = 4) as well as in samples of non-pathological ventricular CSF (V-CSF; n = 4). The results were evaluated with respect to CSF flow rate, as indicated by the albumin quotient (QAlb). The concentrations of prothrombin in L-CSF in NDC (mean: 0.46 mg/1, range: 0.21-0.96), and AD (mean: 0.6 mg/1, range: 0.19-1.2) were in the normal range reported previously. Expectedly, prothrombin concentration in L-CSF of GBS was increased (mean: 6.3 mg/1, range: 2.3-9.7) corresponding to the increased QAlb in this group (mean 54.6 x 10-3, range: 17-88.1). The concentrations of both prothrombin and albumin were 5.5-fold higher in L-CSF than in V-CSF (mean QAlb : 1.1 x 10-3, mean concentration of prothrombin: 0.088 mg/1). In conclusion, CSF prothrombin in all conditions evaluated here is exclusively derived from blood.

Journal of Alzheimer's disease : JAD, 2013

Background: The E4 isoform of the APOE genotype is the most significant genetic risk factor for s... more Background: The E4 isoform of the APOE genotype is the most significant genetic risk factor for sporadic Alzheimer's disease (AD) and has recently been found to modulate disease expression in patients with AD. Objective: To investigate APOE-dependent cognitive and structural phenotypes in subjects with mild cognitive impairment who converted to AD within the following three years.

PLoS ONE, 2011

Background: Today, dementias are diagnosed late in the course of disease. Future treatments have ... more Background: Today, dementias are diagnosed late in the course of disease. Future treatments have to start earlier in the disease process to avoid disability requiring new diagnostic tools. The objective of this study is to develop a new method for the differential diagnosis and identification of new biomarkers of Alzheimer's disease (AD) using capillary-electrophoresis coupled to mass-spectrometry (CE-MS) and to assess the potential of early diagnosis of AD. Methods and Findings: Cerebrospinal fluid (CSF) of 159 outpatients of a memory-clinic at a University Hospital suffering from neurodegenerative disorders and 17 cognitively-healthy controls was used to create differential peptide pattern for dementias and prospective blinded-comparison of sensitivity and specificity for AD diagnosis against the Criterion standard in a naturalistic prospective sample of patients. Sensitivity and specificity of the new method compared to standard diagnostic procedures and identification of new putative biomarkers for AD was the main outcome measure. CE-MS was used to reliably detect 1104 low-molecular-weight peptides in CSF. Training-sets of patients with clinically secured sporadic Alzheimer's disease, frontotemporal dementia, and cognitively healthy controls allowed establishing discriminative biomarker pattern for diagnosis of AD. This pattern was already detectable in patients with mild cognitive impairment (MCI). The AD-pattern was tested in a prospective sample of patients (n = 100) and AD was diagnosed with a sensitivity of 87% and a specificity of 83%. Using CSF measurements of beta-amyloid1-42, total-tau, and phospho 181-tau, AD-diagnosis had a sensitivity of 88% and a specificity of 67% in the same sample. Sequence analysis of the discriminating biomarkers identified fragments of synaptic proteins like proSAAS, apolipoprotein J, neurosecretory protein VGF, phospholemman, and chromogranin A. Conclusions: The method may allow early differential diagnosis of various dementias using specific peptide fingerprints and identification of incipient AD in patients suffering from MCI. Identified biomarkers facilitate face validity for the use in AD diagnosis.

Neurology, 2009

The need for biological markers of Alzheimer disease (AD) is constantly increasing. Proton magnet... more 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. 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. 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. 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.

Molecular Psychiatry, 2008

In this report, we present the results of a multicenter study to test analytic and diagnostic per... more 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 examina-tionX20 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.

Alzheimers & Dementia, Jul 1, 2015

8 and 18 months and to evaluate whether the antiepileptic drug Levetiracetam have any effect on s... more 8 and 18 months and to evaluate whether the antiepileptic drug Levetiracetam have any effect on spontaneous seizures. Methods: Video-EEG/EMG monitoring over 24-hrs of the light dark cycle was carried out at baseline. At 8 months, network excitability was examined by quantifying susceptibility of pentylenetetrazole (PTZ) (30 mg/kg) to induce seizures. At 18 months, the frequency of epileptiform SWD was repeatedly quantified before and after acute and sub-chronic administration of leviracetam (150 mg/kg). Results: At 8 months, APP/PS1 had no spontaneous seizures across different vigilance states. PTZ provoked seizures at shorter latencies in APP/PS1 mice compared to littermate controls, which were associated with a significant increase in EEG power within 4-30 Hz frequency range. These changes were short lasting and rapidly abolished. At 18 months, 60% of APP/PS1 mice expressed spontaneous non-convulsive seizures (30-40s duration) and epileptiform SWD activity at shorter duration i.e. 0.3 -6.0 s. The observed behavioral correlate included motor arrest accompanied by subtle myoclonic jerks. Conclusions: Consistent with previous reports, aged APP/PS1 mice exhibit high incidence of unprovoked epileptic activity, whereas no such abnormalities were detected at a young age. Follow-up studies are underway to investigate whether acute or sub-chronic Levetiracetam can reduce or prevent this epileptiform activity.

Alzheimers & Dementia, Jul 1, 2015

JAMA Psychiatry

; for the International FTD-Genetics Consortium (IFGC), the German Frontotemporal Lobar Degenerat... more ; for the International FTD-Genetics Consortium (IFGC), the German Frontotemporal Lobar Degeneration (FTLD) Consortium, and the PRONIA Consortium IMPORTANCE The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. OBJECTIVE To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). DESIGN, SETTING, AND PARTICIPANTS This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration.

Journal of Neural Transmission

ApoE4, the strongest genetic risk factor for Alzheimer’s disease (AD), has been shown to be asso... more ApoE4, the strongest genetic risk factor for Alzheimer’s disease (AD), has been shown to be associated with both beta-amyloid (Aβ) and tau pathology, with the strongest evidence for effects on Aβ, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aβ42, total tau (t-tau), phospho-tau181 (p-tau), and with the progression of decline in a large cohort of MCI subjects, both progressors to AD and other dementias, as well as non-progressors. We analyzed associations of CSF Aβ42, p-tau and t-tau with ApoE4 allele frequency cross-sectionally and longitudinally over 3 years of follow-up in 195 individuals with a diagnosis of MCI-stable, MCI-AD converters and MCI progressing to other dementias from the German Dementia Competence Network. In the total sample, ApoE4 carriers had lower concentrations of CSF Aβ42, and increased concentrations of t-tau and p-tau compared to non-carriers in a gene dose...


The miRBase-21 database currently lists 1881 microRNA (miRNA) precursors and 2585 unique mature h... more The miRBase-21 database currently lists 1881 microRNA (miRNA) precursors and 2585 unique mature human miRNAs. Since their discovery, miRNAs have proved to present a new level of epigenetic post-transcriptional control of protein synthesis. Initial results point to a possible involvement of miRNA in Alzheimer’s disease (AD). We applied OpenArray technology to profile the expression of 1178 unique miRNAs in cerebrospinal fluid (CSF) samples of AD patients (n = 22) and controls (n = 28). Using a Cq of 34 as cut-off, we identi-fied positive signals for 441 miRNAs, while 729 miRNAs could not be detected, indicating that at least 37 % of miRNAs are present in the brain. We found 74 miRNAs being down-and 74 miRNAs being up-regulated in AD using a 1.5 fold change threshold. By applying the new explorative “Measure of relevance”method, 6 reliable and 9 informative biomarkers were identified. Confirmatory MANCOVA revealed reliablemiR-100, miR-146a and miR-1274a as differentially expressed in ...

Dialogues in Clinical Neuroscience, 2013

Loss of memory is among the first symptoms reported by patients suffering from…

Neurology, Jan 9, 2018

To determine the association of serum neurofilament light chain (NfL) with functional deteriorati... more To determine the association of serum neurofilament light chain (NfL) with functional deterioration and brain atrophy during follow-up of patients with behavioral variant frontotemporal dementia (bvFTD). Blood NfL levels from 74 patients with bvFTD, 26 with Alzheimer disease (AD), 17 with mild cognitive impairment (MCI), and 15 healthy controls (Con) at baseline and follow-up were determined and analyzed for the diagnostic potential in relation to functional assessment (Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB], frontotemporal lobar degeneration-related CDR-SOB, Mini-Mental State Examination [MMSE]) and brain volumetry. At baseline, serum NfL level correlated with CSF NfL (bvFTD = 0.706, < 0.0001; AD/MCI = 0.666, = 0.0003). Highest serum levels were observed in bvFTD ( <0 0.0001 vs Con and MCI, = 0.0078 vs AD, respectively). Discrimination of bvFTD from Con/MCI/AD was possible with 91%/74%/74% sensitivity and 79%/74%/58% specificity. At follow-up, serum NfL increas...

Alzheimer's research & therapy, Jan 25, 2018

With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), inst... more With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), instruments for the follow-up of patients are needed to describe disease progression and to evaluate potential therapeutic effects. So far, volumetric brain changes have been proposed as clinical endpoints in the literature, but cognitive scores are still lacking. This study followed disease progression predominantly in language-based performance within 1 year and defined a PPA sum score which can be used in therapeutic interventions. We assessed 28 patients with nonfluent variant PPA, 17 with semantic variant PPA, 13 with logopenic variant PPA, and 28 healthy controls in detail for 1 year. The most informative neuropsychological assessments were combined to a sum score, and associations between brain atrophy were investigated followed by a sample size calculation for clinical trials. Significant absolute changes up to 20% in cognitive tests were found after 1 year. Semantic and phonemic wor...

PloS one, 2018

Information on circulating miRNAs in frontotemporal lobar degeneration is very limited and confli... more Information on circulating miRNAs in frontotemporal lobar degeneration is very limited and conflicting results have complicated an interpretation in Alzheimer's disease thus far. In the present study we I) collected samples from multiple clinical centers across Germany, II) defined 3 homogenous patient groups with high sample sizes (bvFTD n = 48, AD n = 48 and cognitively healthy controls n = 44), III) compared expression levels in both CSF and serum samples and IV) detected a limited set of miRNAs by using a MIQE compliant protocol based on SYBR-green miRCURY assays that have proven reliable to generate reproducible results. We included several quality controls that identified and reduced technical variation to increase the reliability of our data. We showed that the expression levels of circulating miRNAs measured in CSF did not correlate with levels in serum. Using cluster analysis we found expression pattern in serum that, in part, reflects the genomic organization and affil...

Frontiers in aging neuroscience, 2018

The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosi... more The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to mutation carriers. This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls. Atlas-based volumetry was performed in 13 affected FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status. Compared to sporadic patients, mutation...

Journal of neurology, neurosurgery, and psychiatry, Jan 15, 2017

Neurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mech... more Neurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mechanisms might help in diagnosis, staging and prediction of outcome. We aimed at determining the origin and differential diagnostic and prognostic potential of the putative marker of microglial activation chitotriosidase (CHIT1). Altogether 316 patients were included, comprising patients with sporadic ALS, ALS mimics (disease controls (DCo)), frontotemporal lobar degeneration (FTLD), Creutzfeldt-Jakob disease (CJD), Alzheimer's disease (AD), Parkinson's disease (PD) and healthy controls (Con). CHIT1 and neurofilament levels were determined in cerebrospinal fluid (CSF) and blood and analysed with regard to diagnostic sensitivity and specificity and prognostic performance. Additionally, postmortem tissue was analysed for CHIT1 expression. In ALS, CHIT1 CSF levels were higher compared with Con (p<0.0001), DCo (p<0.05) and neurodegenerative diseases (AD p<0.05, PD p<0.01, F...

Sleep, 2003

Study Objectives: Besides regulating hormone secretion, steroids also modulate sleep architecture... more Study Objectives: Besides regulating hormone secretion, steroids also modulate sleep architecture in specific ways. To simulate a state of altered glucocorticoid-and mineralocorticoid-receptor occupation, we administered metyrapone, an 11-β-hydroxylase inhibitor, that blocks adrenal cortisol synthesis and inhibits the 11-β-hydroxysteroiddehydrogenase type-1 enzyme in the central nervous system and investigated endocrine changes and the sleep electroencephalogram. Design: Each volunteer spent 4 nights in the sleep laboratory, the first of which served to habituate the subject to the conditions in the laboratory. The volunteers underwent 3 trial conditions in random order and in a single-blind design receiving 2 doses of metyrapone (4.5 g or 6.0 g) or placebo on the day before the sleep electroencephalogram recordings. Setting: Sleep laboratory. Participants: 8 healthy male volunteers. Measurements and Results: The corticotropin secretion was significantly enhanced by metyrapone, while the cortisol secretion remained largely unchanged. Growth hormone, progesterone, and dehydroepiandros-terone concentrations were also significantly increased by both doses. Metyrapone induced a pronounced reduction in slow-wave sleep and had slight but nonlinear effects upon rapid eye movement sleep. Parameters of sleep quality were not different between groups. Conclusions: Metyrapone induces pronounced effects on hormonal secretion and the sleep electroencephalogram. These results are in part comparable to those from experiments with the administration of corticotropin-releasing hormone and with experiments that deplete mineralocorticoid receptors. The findings may be explained by altered steroid synthesis proximal to the enzyme block. Metyrapone exerts not only effects upon adrenocortical steroid synthesis, but also important extra-adrenal effects on central corticosteroid metabolism.

Journal of Neuropathology & Experimental Neurology, 2016

The mechanisms leading to amyloid-b (Ab) accumulation in sporadic Alzheimer disease (AD) are unkn... more The mechanisms leading to amyloid-b (Ab) accumulation in sporadic Alzheimer disease (AD) are unknown but both increased production or impaired clearance likely contribute to aggregation. To understand the potential roles of the extracellular matrix proteoglycan Testican-1 in the pathophysiology of AD, we used samples from AD patients and controls and an in vitro approach. Protein expression analysis showed increased levels of Testican-1 in frontal and temporal cortex of AD patients; histological analysis showed that Testican-1 accumulates and co-aggregates with Ab plaques in the frontal, temporal and entorhinal cortices of AD patients. Proteomic analysis identified 10 fragments of Testican-1 in cerebrospinal fluid (CSF) from AD patients. HEK293T cells expressing human wild type or mutant Ab precursor protein (APP) were transfected with Testican-1. The co-expression of both proteins modified the sorting of Testican-1 into the endocytic pathway leading to its transient accumulation in Golgi, which seemed to affect APP processing, as indicated by reduced Ab40 and Ab42 levels in APP mutant cells. In conclusion, patient data reflect a clearance impairment that may favor Ab accumulation in AD brains and our in vitro model supports the notion that the interaction between APP and Testican-1 may be a key step in the production and aggregation of Ab species.

Journal of Alzheimer's disease : JAD, Jan 17, 2015

The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a... more The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials. To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. In patients with MCI, δ based on a broad range of cognitive scales (including the...

Alzheimer's & Dementia, 2014

Background: Research in older adults with subjective cognitive decline (SCD) has mainly focused o... more Background: Research in older adults with subjective cognitive decline (SCD) has mainly focused on Alzheimer's disease (AD)-related MRI markers, such as hippocampal volume. However, small vessel disease (SVD) is currently established as serious comorbidity in dementia and its preliminary stages. It is therefore important to examine SVD markers in addition to AD markers in older adults presenting with SCD. Objective: The aim of our study was to elucidate the role of SVD markers in late middle-aged to older adults with and without SCD in addition to the commonly found role of AD markers (hippocampal volume). Methods: 67 healthy late middle-aged to older adults participated in this study (mean age 68 years); 25 participants with SCD and 42 participants without SCD. We evaluated quantitative as well as qualitative AD markers (i.e., hippocampal volume and medial temporal lobe atrophy (MTA) scale) and SVD markers (i.e., white matter hyperintensities (WMH) volume, Fazekas scale, microbleeds, and lacunar infarcts), and neuropsychological function and amount of memory complaints. Results: We found a significant effect of SCD on hippocampal atrophy, as assessed using the MTA scale, but not on hippocampal volume. In addition, we found a significant effect of SCD, and amount of memory complaints, on WMH volume and Fazekas score, suggesting larger WMH volumes in participants with SCD. Conclusion: SVD MRI markers are related to amount of memory complaints, in addition to the commonly observed AD MRI markers, as demonstrated by the greater WMHs in healthy late middle-aged to older adults with SCD.

Neurochemical Research, 1999

Prothrombin, known to be expressed in brain and to possess growth modulating properties, has been... more Prothrombin, known to be expressed in brain and to possess growth modulating properties, has been suggested to be involved in the pathogenesis of Alzheimer's disease (AD). We studied prothrombin concentration in lumbar CSF (L-CSF) in patients with AD (n = 25), neurologic disease controls (NDC; n = 33) covering a wide range of neurologic disorders, and subjects with Guillain-Barre syndrome (GBS; n = 4) as well as in samples of non-pathological ventricular CSF (V-CSF; n = 4). The results were evaluated with respect to CSF flow rate, as indicated by the albumin quotient (QAlb). The concentrations of prothrombin in L-CSF in NDC (mean: 0.46 mg/1, range: 0.21-0.96), and AD (mean: 0.6 mg/1, range: 0.19-1.2) were in the normal range reported previously. Expectedly, prothrombin concentration in L-CSF of GBS was increased (mean: 6.3 mg/1, range: 2.3-9.7) corresponding to the increased QAlb in this group (mean 54.6 x 10-3, range: 17-88.1). The concentrations of both prothrombin and albumin were 5.5-fold higher in L-CSF than in V-CSF (mean QAlb : 1.1 x 10-3, mean concentration of prothrombin: 0.088 mg/1). In conclusion, CSF prothrombin in all conditions evaluated here is exclusively derived from blood.

Journal of Alzheimer's disease : JAD, 2013

Background: The E4 isoform of the APOE genotype is the most significant genetic risk factor for s... more Background: The E4 isoform of the APOE genotype is the most significant genetic risk factor for sporadic Alzheimer's disease (AD) and has recently been found to modulate disease expression in patients with AD. Objective: To investigate APOE-dependent cognitive and structural phenotypes in subjects with mild cognitive impairment who converted to AD within the following three years.

PLoS ONE, 2011

Background: Today, dementias are diagnosed late in the course of disease. Future treatments have ... more Background: Today, dementias are diagnosed late in the course of disease. Future treatments have to start earlier in the disease process to avoid disability requiring new diagnostic tools. The objective of this study is to develop a new method for the differential diagnosis and identification of new biomarkers of Alzheimer's disease (AD) using capillary-electrophoresis coupled to mass-spectrometry (CE-MS) and to assess the potential of early diagnosis of AD. Methods and Findings: Cerebrospinal fluid (CSF) of 159 outpatients of a memory-clinic at a University Hospital suffering from neurodegenerative disorders and 17 cognitively-healthy controls was used to create differential peptide pattern for dementias and prospective blinded-comparison of sensitivity and specificity for AD diagnosis against the Criterion standard in a naturalistic prospective sample of patients. Sensitivity and specificity of the new method compared to standard diagnostic procedures and identification of new putative biomarkers for AD was the main outcome measure. CE-MS was used to reliably detect 1104 low-molecular-weight peptides in CSF. Training-sets of patients with clinically secured sporadic Alzheimer's disease, frontotemporal dementia, and cognitively healthy controls allowed establishing discriminative biomarker pattern for diagnosis of AD. This pattern was already detectable in patients with mild cognitive impairment (MCI). The AD-pattern was tested in a prospective sample of patients (n = 100) and AD was diagnosed with a sensitivity of 87% and a specificity of 83%. Using CSF measurements of beta-amyloid1-42, total-tau, and phospho 181-tau, AD-diagnosis had a sensitivity of 88% and a specificity of 67% in the same sample. Sequence analysis of the discriminating biomarkers identified fragments of synaptic proteins like proSAAS, apolipoprotein J, neurosecretory protein VGF, phospholemman, and chromogranin A. Conclusions: The method may allow early differential diagnosis of various dementias using specific peptide fingerprints and identification of incipient AD in patients suffering from MCI. Identified biomarkers facilitate face validity for the use in AD diagnosis.

Neurology, 2009

The need for biological markers of Alzheimer disease (AD) is constantly increasing. Proton magnet... more 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. 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. 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. 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.

Molecular Psychiatry, 2008

In this report, we present the results of a multicenter study to test analytic and diagnostic per... more 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 examina-tionX20 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.