| 1. |
- De Meyer, Geert, et al.
(author)
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Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people.
- 2010
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In: Archives of neurology. - : American Medical Association (AMA). - 1538-3687 .- 0003-9942. ; 67:8, s. 949-56
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, unsupervised way, without using information on the clinical diagnosis. DESIGN: Mixture modeling approach. SETTING: Alzheimer's Disease Neuroimaging Initiative database. Patients or Other PARTICIPANTS: Cognitively normal persons, patients with AD, and individuals with mild cognitive impairment. MAIN OUTCOME MEASURES: Cerebrospinal fluid-derived beta-amyloid protein 1-42, total tau protein, and phosphorylated tau(181P) protein concentrations were used as biomarkers on a clinically well-characterized data set. The outcome of the qualification analysis was validated on 2 additional data sets, 1 of which was autopsy confirmed. RESULTS: Using the US Alzheimer's Disease Neuroimaging Initiative data set, a cerebrospinal fluid beta-amyloid protein 1-42/phosphorylated tau(181P) biomarker mixture model identified 1 feature linked to AD, while the other matched the "healthy" status. The AD signature was found in 90%, 72%, and 36% of patients in the AD, mild cognitive impairment, and cognitively normal groups, respectively. The cognitively normal group with the AD signature was enriched in apolipoprotein E epsilon4 allele carriers. Results were validated on 2 other data sets. In 1 study consisting of 68 autopsy-confirmed AD cases, 64 of 68 patients (94% sensitivity) were correctly classified with the AD feature. In another data set with patients (n = 57) with mild cognitive impairment followed up for 5 years, the model showed a sensitivity of 100% in patients progressing to AD. CONCLUSIONS: The mixture modeling approach, totally independent of clinical AD diagnosis, correctly classified patients with AD. The unexpected presence of the AD signature in more than one-third of cognitively normal subjects suggests that AD pathology is active and detectable earlier than has heretofore been envisioned.
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| 2. |
- De Meyer, Geert, et al.
(author)
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Diagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People
- 2010
-
In: Archives of Neurology. - 0003-9942. ; 67:8, s. 949-956
-
Journal article (peer-reviewed)abstract
- Objective: To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, unsupervised way, without using information on the clinical diagnosis. Design: Mixture modeling approach. Setting: Alzheimer's Disease Neuroimaging Initiative database. Patients or Other Participants: Cognitively normal persons, patients with AD, and individuals with mild cognitive impairment. Main Outcome Measures: Cerebrospinal fluid derived p-amyloid protein 1-42, total tau protein, and phosphorylated tau(181p) protein concentrations were used as biomarkers on a clinically well-characterized data set. The outcome of the qualification analysis was validated on 2 additional data sets, 1 of which was autopsy confirmed. Results: Using the US Alzheimer's Disease Neuroimaging Initiative data set, a cerebrospinal fluid beta-amyloid protein 1-42/phosphorylated tau(181P) biomarker mixture model identified 1 feature linked to AD, while the other matched the "healthy" status. The AD signature was found in 90%, 72%, and 36% of patients in the AD, mild cognitive impairment, and cognitively normal groups, respectively. The cognitively normal group with the AD signature was enriched in apolipoprotein E 64 allele carriers. Results were validated on 2 other data sets. In 1 study consisting of 68 autopsy-confirmed AD cases, 64 of 68 patients (94% sensitivity) were correctly classified with the AD feature. In another. data set with patients (n=57) with mild cognitive impairment followed up for 5 years, the model showed a sensitivity of 100% in patients progressing to AD. Conclusions: The mixture modeling approach, totally independent of clinical AD diagnosis, correctly classified patients with AD. The unexpected presence of the AD signature in more than one-third of cognitively normal subjects suggests that AD pathology is active and detectable earlier than has heretofore been envisioned.
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| 3. |
- Dubois, Bruno, et al.
(author)
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Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria.
- 2014
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In: Lancet neurology. - 1474-4465. ; 13:6, s. 614-29
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Research review (peer-reviewed)abstract
- In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
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| 4. |
- Gallagher, Michael D., et al.
(author)
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TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions
- 2014
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 127:3, s. 407-418
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Journal article (peer-reviewed)abstract
- Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
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| 5. |
- Lambert, Jean-Charles, et al.
(author)
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The CALHM1 P86L Polymorphism is a Genetic Modifier of Age at Onset in Alzheimer's Disease : a Meta-Analysis Study
- 2010
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 22:1, s. 247-255
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Journal article (peer-reviewed)abstract
- The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the epsilon 4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the epsilon 4 allele of the APOE gene.
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