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1.  β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage 
The β-secretase enzyme, β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in the first step in β-amyloid (Aβ) peptide production. Thus, BACE1 is a key target for candidate disease-modifying treatment of Alzheimer’s disease. In a previous exploratory Aβ biomarker study, we found that BACE1 inhibitor treatment resulted in decreased levels of Aβ1-34 together with increased Aβ5-40, suggesting that these Aβ species may be novel pharmacodynamic biomarkers in clinical trials. We have now examined whether the same holds true in humans.
In an investigator-blind, placebo-controlled and randomized study, healthy subjects (n =18) were randomly assigned to receive a single dose of 30 mg of LY2811376 (n =6), 90 mg of LY2811376 (n =6), or placebo (n =6). We used hybrid immunoaffinity-mass spectrometry (HI-MS) and enzyme-linked immunosorbent assays to monitor a variety of Aβ peptides.
Here, we demonstrate dose-dependent changes in cerebrospinal fluid (CSF) Aβ1-34, Aβ5-40 and Aβ5-X after treatment with the BACE1-inhibitor LY2811376. Aβ5-40 and Aβ5-X increased dose-dependently, as reflected by two independent methods, while Aβ1-34 dose-dependently decreased.
Using HI-MS for the first time in a study where subjects have been treated with a BACE inhibitor, we confirm that CSF Aβ1-34 may be useful in clinical trials on BACE1 inhibitors to monitor target engagement. Since it is less hydrophobic than longer Aβ species, it is less susceptible to preanalytical confounding factors and may thus be a more stable marker. By independent measurement techniques, we also show that BACE1 inhibition in humans is associated with APP-processing into N-terminally truncated Aβ peptides via a BACE1-independent pathway.
Trial registration NCT00838084. Registered: First received: January 23, 2009, Last updated: July 14, 2009, Last verified: July 2009.
PMCID: PMC4233234  PMID: 25404952
2.  Levels of cerebrospinal fluid α-synuclein oligomers are increased in Parkinson’s disease with dementia and dementia with Lewy bodies compared to Alzheimer’s disease 
The objective was to study whether α-synuclein oligomers are altered in the cerebrospinal fluid (CSF) of patients with dementia, including Parkinson disease with dementia (PDD), dementia with Lewy bodies (DLB), and Alzheimer disease (AD), compared with age-matched controls.
In total, 247 CSF samples were assessed in this study, including 71 patients with DLB, 30 patients with PDD, 48 patients with AD, and 98 healthy age-matched controls. Both total and oligomeric α-synuclein levels were evaluated by using well-established immunoassays.
The levels of α-synuclein oligomers in the CSF were increased in patients with PDD compared with the controls (P < 0.05), but not in patients with DLB compared with controls. Interestingly, the levels of α-synuclein oligomers in the CSF were also significantly higher in patients with PDD (P < 0.01) and DLB (P < 0.05) compared with patients with AD. The levels of CSF α-synuclein oligomers and the ratio of oligomeric/total-α-synuclein could distinguish DLB or PDD patients from AD patients, with areas under the curves (AUCs) of 0.64 and 0.75, respectively. In addition, total-α-synuclein alone could distinguish DLB or PDD patients from AD patients, with an AUC of 0.80.
The levels of α-synuclein oligomers were increased in the CSF from α-synucleinopathy patients with dementia compared with AD cases.
PMCID: PMC4075410  PMID: 24987465
3.  Performance on a pattern separation task by Alzheimer’s patients shows possible links between disrupted dentate gyrus activity and apolipoprotein E ∈4 status and cerebrospinal fluid amyloid-β42 levels 
Emerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer’s disease (AD). In mice, adult neurogenesis is reduced by knock-in alleles for human apolipoprotein E (ApoE) ∈4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in the triple-transgenic mouse model of AD (3xTg-AD); this reduction being directly associated with the presence of amyloid-β (Aβ) plaques and an increase in the number of Aβ-containing neurons in the hippocampus. Cognitive tasks involving difficult pattern separations have been shown to reflect DG activity and thus potentially neurogenesis in both animals and man. This study involved the administration of a pattern separation paradigm to Alzheimer’s patients to investigate relationships between task performance and both ApoE status and cerebrospinal fluid (CSF) Aβ42 levels.
The CDR System pattern separation task involves the presentation of pictures that must later be discriminated from closely similar pictures. This paper presents pattern separation data from 66 mild to moderate AD patients, of which 50 were genotyped and 65 in whom CSF Aβ42 was measured.
ApoE ∈4 homozygotes were not compromised on the easy pattern separations compared with the other patients, but they were statistically significantly poorer at the difficult separations. In all patients CSF Aβ42 correlated significantly with the ability to make the difficult discriminations, but not easier discriminations. Pattern separation speed correlated negatively with CSF Aβ42, and thus the association was not due to increased impulsivity.
These are, to our knowledge, the first human pattern separation data to suggest a possible genetic link to poor hippocampal neurogenesis in AD, as well as a relationship to Aβ42. Therapies which target neurogenesis may thus be useful in preventing the early stages of AD, notably in ApoE ∈4 homocygotes.
PMCID: PMC4054957  PMID: 24735568
4.  Cerebrospinal fluid biomarkers for Alzheimer disease and subcortical axonal damage in 5,542 clinical samples 
The neuronal loss in Alzheimer disease (AD) has been described to affect grey matter in the cerebral cortex. However, in the elderly, AD pathology is likely to occur together with subcortical axonal degeneration on the basis of cerebrovascular disease. Therefore, we hypothesized that biomarkers for AD and subcortical axonal degeneration would correlate in patients undergoing testing for dementia biomarkers, particularly in older age groups.
We performed correlation and cluster analyses of cerebrospinal fluid (CSF) biomarker data from 5,542 CSF samples analyzed in our routine clinical neurochemistry laboratory in 2010 through 2012 for the established CSF AD biomarkers total tau (T-tau), phosphorylated-tau (P-tau), amyloid β1-42 (Aβ42), and for neurofilament light (NFL), which is a protein expressed in large-caliber myelinated axons, the CSF levels of which correlate with subcortical axonal injury.
Aβ42, T-tau, and P-tau correlated with NFL. By cluster analysis, we found a bimodal data distribution in which a group with a low Aβ42/P-tau ratio (suggesting AD pathology) had high levels of NFL. High levels of NFL also correlated with the presence of an AD biomarker pattern defined by Aβ42/P-tau and T-tau. Only 29% of those with an AD biomarker signature had normal NFL levels. Age was a possible confounding factor for the associations between NFL and established AD biomarkers, but in a logistic regression analysis, both age and NFL independently predicted the AD biomarker pattern.
The association between an AD-like signature using the established biomarkers Aβ42, T-tau, and P-tau with increased levels of NFL provides in vivo evidence of an association between AD and subcortical axonal degeneration in this uniquely large dataset of CSF samples tested for dementia biomarkers.
PMCID: PMC3978733  PMID: 24479774
6.  Dose and plasma concentration of galantamine in Alzheimer's disease - clinical application 
Patients with Alzheimer's disease (AD) are currently treated with cholinesterase inhibitors, such as galantamine, without actual knowledge of its concentration in plasma. Our objective was to analyse potential relationships between galantamine concentration, galantamine dose, socio-demographic characteristics, body weight, body mass index (BMI), and treatment response.
Eighty-four patients with AD recruited from the Memory Clinic, Malmö, Sweden, and treated with galantamine were included in the study. Efficacy measures, including cognition (Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog)) and instrumental activities of daily living (IADL), were evaluated at baseline, 2 months after treatment initiation (MMSE only) and semi-annually over 3 years. At these assessments, blood samples were obtained for the analysis of the galantamine concentration, and body weight, BMI, drug dose and time from drug intake were recorded.
All patients had a measurable concentration of galantamine at all assessments. The mean plasma concentration of the drug exhibited a positive linear association with dose (r = 0.513, P < 0.001). The dose did not differ between sexes. Negative linear associations between the galantamine plasma concentration and BMI (r = -0.454, P = 0.001) or body weight (r = -0.310, P = 0.034) were found exclusively in the male group. When mixed-effects models were used, the dose of galantamine (P < 0.001), time from drug intake (P < 0.001), and BMI (P = 0.021) or weight (P = 0.002) were factors that predicted the concentration, whereas sex, age, and cognitive and functional changes were not.
High compliance to galantamine treatment was found among all patients in this naturalistic AD study. The impact of BMI or body weight on the plasma concentration of galantamine was important only among males. No relationship was observed between concentration and short-term treatment response or progression rate in terms of cognitive and functional abilities.
PMCID: PMC3580330  PMID: 23286718
7.  Use of theragnostic markers to select drugs for phase II/III trials for Alzheimer disease 
In a slowly progressive disorder like Alzheimer disease, evaluation of the clinical effect of novel drug candidates requires large numbers of patients and extended treatment periods. Current cell- and animal-based disease models of Alzheimer disease are poor at predicting a positive treatment response in patients. To help bridge the gap between disease models and large and costly clinical trials with high failure rates, biomarkers for the intended biochemical drug effect may be of value. Such biomarkers may be called 'theragnostic'. Here, we review the literature addressing the prospective value of these biomarkers.
PMCID: PMC3031878  PMID: 21122172
8.  Is it time for biomarker-based diagnostic criteria for prodromal Alzheimer's disease? 
Drug candidates targeting amyloid-β (Aβ) pathology in Alzheimer's disease are in different phases of clinical trials. These treatments will probably be most effective in the earlier stages of the disease, before neurodegeneration is too severe, but at the same time symptoms are vague and the clinical diagnosis is difficult. Recent research advances have resulted in promising biomarkers, including cerebrospinal fluid analyses for tau and Aβ, magnetic resonance imaging measurement of atrophy, and positron emission tomography imaging of glucose metabolism and Aβ pathology, which allow identification of prodromal Alzheimer's disease. More details are needed, however, on how these biomarkers can be standardized, to allow a general implementation in the clinical routine diagnostic work-up of patients with cognitive disturbances.
PMCID: PMC2876786  PMID: 20441609
9.  A novel Aβ isoform pattern in CSF reflects γ-secretase inhibition in Alzheimer disease 
LY450139 (semagacestat) inhibits γ-secretase, a key enzyme for generation of amyloid β (Aβ), the peptide deposited in plaques in Alzheimer disease (AD). Previous data have shown that LY450139 lowers plasma Aβ, but has no clear effect on Aβ1-40 or Aβ1-42 levels in cerebrospinal fluid (CSF). By using targeted proteomics techniques, we recently identified several shorter Aβ isoforms, such as Aβ1-16, that in experimental settings increase during γ-secretase inhibitor treatment, and thus may serve as sensitive biochemical indices of the treatment effect. Here, we test the hypothesis that these shorter Aβ isoforms may be biomarkers of γ-secretase inhibitor treatment in clinical trials.
In a phase II clinical trial, 35 individuals with mild to moderate AD were randomized to placebo (n = 10) or LY450139 (100 mg (n = 15) or 140 mg (n = 10)) and underwent lumbar puncture at baseline and after 14 weeks of treatment. The CSF Aβ isoform pattern was analyzed with immunoprecipitation combined with MALDI-TOF mass spectrometry.
The CSF levels of Aβ1-14, Aβ1-15, and Aβ1-16 showed a dose-dependent increase by 57% and 74%, 21% and 35%, and 30% and 67%, respectively in the 100-mg and 140-mg treatment groups. Aβ1-40 and Aβ1-42 were unaffected by treatment.
CSF Aβ1-14, Aβ1-15, and Aβ1-16 increase during γ-secretase inhibitor treatment in AD, even at doses that do not affect Aβ1-42 or Aβ1-40, probably because of increased substrate availability of the C99 APP stub (APP β-CTF) induced by γ-secretase inhibition. These Aβ isoforms may be novel sensitive biomarkers to monitor the biochemical effect in clinical trials.
Trial registration
Clinical NCT00244322
PMCID: PMC2876785  PMID: 20350302

Results 1-9 (9)