| 1. |
- Andreasson, U., et al.
(författare)
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An enzyme activity as a potential biomarker for Alzheimer's disease.
- 2010
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 6:4, s. 497-498
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Konferensbidrag (refereegranskat)abstract
- Background: Six different N-terminal amyloid precursor protein (APP) fragments, with molecular weight ∼12 kDa, have previously been identified in human cerebrospinal fluid (CSF). In a pilot study, both the sum of their concentrations, measured by western blot, and the relative abundance pattern, measured by mass spectrometry, were different in Alzheimer's disease (AD) patients compared to healthy controls. To test if these differences were also reflected in protease activities that possibly give rise to the ∼12 kDa fragments an enzymatic assay was developed and the activity in CSF was investigated for its potential as a biomarker for AD. Methods: The substrate in the protease activity assay was a custom made fluorochrome/quencher labeled peptide that covers the cleavage sites in APP (APP118-APP127) corresponding to the C-termini of the six ∼12 kDa APP fragments. The activity was measured in CSF from 55 AD patients and 17 controls. Results: There was a significant increase in the protease activity in CSF from AD patients compared to the controls (p = 0.001). This is in line with previous results which indicate that the sum of the ∼12 kDa fragments are elevated in AD. Results from inhibition studies strongly suggests that the enzyme responsible for the cleavage of the substrate is an aspartic protease since a sub nM IC50 value was recorded for Pepstatin A while no inhibition was observed for the cysteine protease specific inhibitor E64 at concentrations up to100 nM. Conclusions: There exists an enzymatic activity in CSF capable of cleaving a peptide substrate that spans a portion, close to the N-terminal, of APP. In a pilot study the activity is increased in AD patients compared to controls suggesting that it can be used as a biomarker.
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| 2. |
- Bell, Joanne, et al.
(författare)
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A novel BACE inhibitor (PF-05297909): : A two-part adaptive design to evaluate safety, pharmacokinetics and pharmacodynamics for modifying beta-amyloid in a first-in-human study
- 2013
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 9:4, s. P287-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe accumulation of amyloid beta (Aβ) peptides is believed to be a central contributor to the neurodegeneration seen in the Alzheimer's disease (AD) brain. Given the central role of Aβ42 in AD pathogenesis, a therapeutic strategy to lower central Aβ42 (and Aβ40) levels via inhibition of BACE was adopted in a first in human trial in a 2-part adaptive design.MethodsPart 1 evaluated PF-05297909 plasma PK and the PK/PD relationship for the reduction of plasma Aβ40, Aβ42 and AβX levels; Part 2 evaluated the exposure-response relationship between PF-05297909 and CSF levels of Aβ40, Aβ42 and AβX. Sufficient safety and tolerability, plasma exposure and reduction in plasma Aβ were necessary to initiate Part 2. Part 1 was a sequential parallel group dose escalation (25, 100, 250 and 325 mg) with n=8 (6:2, active:placebo) healthy volunteers (HV) in each cohort. Part 2 consisted of 3 cohorts of n=8 (6:2, active:placebo) HV. Doses selected for Part 2 started with the highest safe dose in Part 1 and then adapted for subsequent cohorts. The PK/PD relationship between PF-05297909 and Aβ42 was determined using a non-linear mixed effects (NLME) analysis. The doses for Part 2 - cohort 2 and 3 were to be chosen to improve the relative standard error in the estimate of the BACE IC50 as quantified by evaluating the determinant of the Fisher information matrix for the NLME model.ResultsPF-05297909 was well-tolerated. Reduction in plasma Aβ (Aβ40 and Aβ42) was exposure related with an apparent maximum at the 250 mg dose with a greater duration of activity at the 325 mg dose of PF-05297909. A 325 mg dose was selected for Part 2 - cohorts 1 and 2 without further cohorts being run, as stopping criteria for futility were met following analysis of cohort 2. A PK/PD relationship in CSF was not observed.ConclusionsThe adaptive designed PF-05297909 FIH study allowed efficient testing of safety and of the PK/PD relationship between PF-05297909 exposure and Aβ (Aβ40 and Aβ42). PF-05297909 was safe and well tolerated in HV at exposures tested. A robust effect on plasma Aβ did not translate to CSF pharmacodynamic effects.
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| 3. |
- Brunnström, Hans, et al.
(författare)
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Cerebrospinal fluid biomarker results in relation to neuropathological dementia diagnoses.
- 2010
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Ingår i: Alzheimer's & dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 6:2, s. 104-109
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Clinical dementia diagnoses are not always consistent with neuropathological findings. As correct diagnosis is important for treatment and care, new diagnostic possibilities for dementia are in demand. Cerebrospinal fluid biomarkers should ideally be able to identify ongoing processes in the brain, but need to be further compared with neuropathological findings for evaluation of their diagnostic validity. METHODS: This study included 43 patients with a clinical dementia disorder. All patients were neuropathologically examined at the University Hospital in Lund, Sweden, during the years 2001-2008, and all had a lumbar puncture carried out as part of the clinical investigation during the time of cognitive impairment. RESULTS: Of eight patients, five with Alzheimer's disease had elevated total tau protein (T-tau) and decreased amyloid beta 1-42 protein (Abeta42), while both values for the other three patients were normal. Slightly elevated T-tau and/or decreased Abeta42 were also seen in several patients with other dementia diagnoses such as Lewy body disease, frontotemporal lobar degeneration and vascular dementia. Furthermore, T-tau levels did not differ markedly between patients with morphologically tau-positive and tau-negative frontotemporal lobar degeneration. Also, seven of nine patients with Creutzfeldt-Jacob disease exhibited pronounced elevation in T-tau concentration. CONCLUSION: From this rather limited study, being the first of its kind in Sweden, we may conclude that there is no perfect concordance between cerebrospinal fluid biomarker levels and pathological findings, which should be taken into account in the clinical diagnostic setting.
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| 4. |
- Carrillo, Maria C, et al.
(författare)
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Global standardization measurement of cerebral spinal fluid for Alzheimer's disease: an update from the Alzheimer's Association Global Biomarkers Consortium.
- 2013
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 9:2, s. 137-40
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Tidskriftsartikel (refereegranskat)abstract
- Recognizing that international collaboration is critical for the acceleration of biomarker standardization efforts and the efficient development of improved diagnosis and therapy, the Alzheimer's Association created the Global Biomarkers Standardization Consortium (GBSC) in 2010. The consortium brings together representatives of academic centers, industry, and the regulatory community with the common goal of developing internationally accepted common reference standards and reference methods for the assessment of cerebrospinal fluid (CSF) amyloid β42 (Aβ42) and tau biomarkers. Such standards are essential to ensure that analytical measurements are reproducible and consistent across multiple laboratories and across multiple kit manufacturers. Analytical harmonization for CSF Aβ42 and tau will help reduce confusion in the AD community regarding the absolute values associated with the clinical interpretation of CSF biomarker results and enable worldwide comparison of CSF biomarker results across AD clinical studies.
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| 5. |
- Chincarini, Andrea, et al.
(författare)
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Automatic temporal lobe atrophy assessment in prodromal AD: Data from the DESCRIPA study
- 2014
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 10:4, s. 456-467
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the framework of the clinical validation of research tools, this investigation presents a validation study of an automatic medial temporal lobe atrophy measure that is applied to a naturalistic population sampled from memory clinic patients across Europe. Methods: The procedure was developed on 1.5-T magnetic resonance images from the Alzheimer's Disease Neuroimaging Initiative database, and it was validated on an independent data set coming from the DESCRIPA study. All images underwent an automatic processing procedure to assess tissue atrophy that was targeted at the hippocampal region. For each subject, the procedure returns a classification index. Once provided with the clinical assessment at baseline and follow-up, subjects were grouped into cohorts to assess classification performance. Each cohort was divided into converters (co) and nonconverters (nc) depending on the clinical outcome at follow-up visit. Results: We found the area under the receiver operating characteristic curve (AUC) was 0.81 for all co versus nc subjects, and AUC was 0.90 for subjective memory complaint (SMCnc) versus all co subjects. Furthermore, when training on mild cognitive impairment (MCI-nc/MCI-co), the classification performance generally exceeds that found when training on controls versus Alzheimer's disease (CTRL/AD). Conclusions: Automatic magnetic resonance imaging analysis may assist clinical classification of subjects in a memory clinic setting even when images are not specifically acquired for automatic analysis. (C) 2014 The Alzheimer's Association. All rights reserved.
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| 6. |
- Duits, Flora H., et al.
(författare)
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The cerebrospinal fluid "Alzheimer profile": Easily said, but what does it mean?
- 2014
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Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 10:6, s. 713-723
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-beta(1-42) (A beta(42)), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimers disease (AD). Methods: We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442). Results: Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/A beta(42) ratio and 0.08 for the p-tau/A beta(42) ratio. Ratios performed similar to formulas (sensitivity, 91%-93%; specificity, 81%-84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/A beta(42) ratio. Conclusions: A tau/A beta(42) ratio of greater than0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.
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| 7. |
- Durazzo, T. C., et al.
(författare)
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Smoking and increased Alzheimer's disease risk: A review of potential mechanisms
- 2014
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 10:3 SUPPL., s. S122-S145
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Tidskriftsartikel (refereegranskat)abstract
- Background Cigarette smoking has been linked with both increased and decreased risk for Alzheimer's disease (AD). This is relevant for the US military because the prevalence of smoking in the military is approximately 11% higher than in civilians. Methods A systematic review of published studies on the association between smoking and increased risk for AD and preclinical and human literature on the relationships between smoking, nicotine exposure, and AD-related neuropathology was conducted. Original data from comparisons of smoking and never-smoking cognitively normal elders on in vivo amyloid imaging are also presented. Results Overall, literature indicates that former/active smoking is related to a significantly increased risk for AD. Cigarette smoke/smoking is associated with AD neuropathology in preclinical models and humans. Smoking-related cerebral oxidative stress is a potential mechanism promoting AD pathology and increased risk for AD. Conclusions A reduction in the incidence of smoking will likely reduce the future prevalence of AD.
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| 8. |
- Elobeid, Adila, et al.
(författare)
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Alzheimer's disease-related plaques in nondemented subjects
- 2014
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 10:5, s. 522-529
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) pathology was assessed in 587 nondemented subjects, with age at death at or more than 50 years. In 307 subjects, amyloid-beta (A beta) immunoreactive (IR) plaques were seen; in 192 subjects, neuritic plaques (NPs) stained with modified Bielschowsky silver stain (mBky) were observed. In 20% of the whole cohort and in 62% of the 192 subjects with NPs in mBky, hyperphosphorylated tau (HPtau) IR NPs were seen. In most cases in this nondemented cohort, the HPtau IR NPs were observed either sparsely or to a moderate extent. The correlation between the NP score and Braak stage was best (r = 0.6, P < .001) when HPtau immunohistochemistry was used. Eighty-three percent of the subjects could not be categorized following the 1997 National Institute on Aging and the Reagan Institute (NIA-RI) recommendations, whereas the 2012 National Institute on Aging Alzheimer's Association (NIA-AA) guidelines were applicable for all study subjects. Twenty-eight subjects had an intermediate level of AD neuropathological change according to the 2012 NIA-AA guidelines, and 25 of these 28 subjects displayed HPtau IR NPs in the temporal cortex. It is noteworthy, however, that as many as 119 out of the 192 subjects with NPs in mBky displayed HPtau IR NPs in the temporal cortex. Ninety-four of these 119 subjects with neocortical HPtau IR NPs had a low level of neuropathological AD change according to the 2012 NIA-AA guidelines because they were in Braak stages I and II. Thus, 94 subjects were not acknowledged as being at risk for AD when applying the 2012 NIA-AA guidelines. We suggest that to identify all subjects with cortical HPtau pathology and, consequently, probably being at risk for developing AD, in addition to the level of AD neuropathological change as recommended by the 2012 NIA-AA guidelines, assessment of HPtau IR NPs in the neocortex should be carried out.
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| 9. |
- Exalto, Lieza G, et al.
(författare)
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Midlife risk score for the prediction of dementia four decades later
- 2013
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 10:5, s. 562-570
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveThe objective of this study was to obtain external validation of the only available midlife dementia risk score cardiovascular risk factors , aging and dementia study (CAIDE) constituting age, education, hypertension, obesity, and hyperlipidemia in a larger, more diverse population. Our second aim was to improve the CAIDE risk score by additional midlife risk factors.MethodsThis retrospective cohort study was conducted in an integrated health care delivery system. A total of 9480 Kaiser Permanente members who participated in a health survey study (age range, 40–55 years) from 1964 to 1973 were included in this study. Dementia diagnoses from primary care and medical specialist visits were collected from January 1, 1994 to January 16, 2006, using International Classification of Diseases 9 codes 290.0, 290.1 for “possible dementia,” and 331.0 and 290.4 for “specialist confirmed dementia.” Risk model prediction and validation were examined with the C statistic, net reclassification improvement, and integrated discrimination improvement. Dementia risk per sum score was calculated with Kaplan-Meier estimates.ResultsA total of 2767 participants (25%) were diagnosed with any type of dementia, of which 1011 diagnoses (10.7%) were specialist-confirmed diagnoses. Average time between midlife examination and end of follow-up was 36.1 years. The CAIDE risk score replicated well with a C statistic of 0.75, quite similar to the original CAIDE C statistic of 0.78. The CAIDE score also predicted well within different race strata. Other midlife risk factors (central obesity, depressed mood, diabetes mellitus, head trauma, lung function, and smoking) did not improve predictability. The risk score allowed stratification of participants into those with 40-year low (9%) and high (29%) dementia risk.ConclusionsA combination of modifiable vascular risk factors in midlife is highly predictive of the likelihood of dementia decades later. Possible dementia prevention strategies should point to a life course perspective on maintaining vascular health.
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