Biomarkers in AlzSWAN

The increasing age of populations in the developed world is associated with a dramatic rise in dementia-related disorders such as Alzheimer disease (AD). As current state-of-the-art diagnostics for these disorders are invasive (lumbar puncture), expensive (MRI and PET amyloid imaging) and time-consuming (comprehensive examination at specialist clinics), they have limited utility as high-throughput, or front-line, screening tools. Avalible online

In Big Picture, Familial AD’s Biomarker Data Resemble LOAD

Researchers with eyes peeled toward prodromal Alzheimer’s disease probably see this diagram in their sleep—the one where the field’s five most validated markers trace their poignant path from normal cognition to fully developed AD. Two research groups proposed this theoretical model some years ago (see Perrin et al., 2009; Jack et al., 2010). But is it true? At least in its broad strokes, the answer seems to be yes, according to early data pouring in from biomarker studies in autosomal-dominant AD. By and large, brain amyloid, brain metabolism, atrophy, and functional connectivity data from independent analyses of theDominantly Inherited Alzheimer Network (DIAN) and the Alzheimer’s Prevention Initiative (API) jibe with each other and confirm the sequence of preclinical biomarker changes proposed for late-onset AD. This article highlights DIAN and API neuroimaging results reported 14-19 July 2012 at the Alzheimer’s Association International Conference (AAIC) in Vancouver, Canada.

CSF Markers: Goodbye, Research Use Only; Hello, Clinical

This is Part 1 of a two-part series. See also Part 2.
What a difference a year can make. At the 2011 Alzheimer’s Association International Conference in Paris, France, leading scientists in the CSF Alzheimer’s biomarker field met to tackle the vexing problem of measurement variability with the available commercial assays. Alas, back then a listener could be forgiven for thinking of the Tower of Babel, as groups presented their own stance and talked past each other as much as finding common ground.

On the different clinical presentations of AD

AD may have different clinical presentations depending on the area where the neurodegeneration starts first. The more frequent region is the medial temporal lobe, affecting the hippocampus but there are variants starting in the frontal lobe (frontal AD) and parieto-occipital (posterior AD).
Analyses of cortical thickness patterns support the hypothesis that different clinical presentations of AD represent points in a phenotypic spectrum of neuroanatomical variation (Ridway). 
However, serum anti-Aβ IgG1 and IgG3 antibodies differ between distinct forms of AD. Its significance is discussed for possible implications as immune effectors in the specific pathophysiology of AD variants (Dorothée).

Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD

OBJECTIVE:

To compare the diagnostic performance of PET with the amyloid ligand Pittsburgh compound B (PiB-PET) to fluorodeoxyglucose (FDG-PET) in discriminating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD).

METHODS:

Patients meeting clinical criteria for AD (n = 62) and FTLD (n = 45) underwent PiB and FDG-PET. PiB scans were classified as positive or negative by 2 visual raters blinded to clinical diagnosis, and using a quantitative threshold derived from controls (n = 25). FDG scans were visually rated as consistent with AD or FTLD, and quantitatively classified based on the region of lowest metabolism relative to controls.

RESULTS:

PiB visual reads had a higher sensitivity for AD (89.5% average between raters) than FDG visual reads (77.5%) with similar specificity (PiB 83%, FDG 84%). When scans were classified quantitatively, PiB had higher sensitivity (89% vs 73%) while FDG had higher specificity (83% vs 98%). On receiver operating characteristic analysis, areas under the curve for PiB (0.888) and FDG (0.910) were similar. Interrater agreement was higher for PiB (κ = 0.96) than FDG (κ = 0.72), as was agreement between visual and quantitative classification (PiB κ = 0.88-0.92; FDG κ = 0.64-0.68). In patients with known histopathology, overall classification accuracy (2 visual and 1 quantitative classification per patient) was 97% for PiB (n = 12 patients) and 87% for FDG (n = 10).

CONCLUSIONS:

PiB and FDG showed similar accuracy in discriminating AD and FTLD. PiB was more sensitive when interpreted qualitatively or quantitatively. FDG was more specific, but only when scans were classified quantitatively. PiB slightly outperformed FDG in patients with known histopathology.

 Neurology. 2011 Dec 6;77(23):2034-42

Age and diagnostic performance of Alzheimer disease CSF biomarkers

OBJECTIVES:

Core CSF changes in Alzheimer disease (AD) are decreased amyloid β(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly.

METHODS:

We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis.

RESULTS:

The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages.

CONCLUSION:

Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

Revised Criteria for Mild Cognitive Impairment May Compromise the Diagnosis of Alzheimer Disease Dementia.

OBJECTIVE:

To evaluate the potential impact of revised criteria for mild cognitive impairment (MCI), developed by a work group sponsored by the National Institute on Aging and the Alzheimer's Association, on the diagnosis of very mild and mild Alzheimer disease (AD) dementia.

DESIGN:

Retrospective review of ratings of functional impairment across diagnostic categories.

SETTING:

Alzheimer's Disease Centers and the National Alzheimer's Coordinating Center.

PARTICIPANTS:

Individuals (N = 17 535) with normal cognition, MCI, or AD dementia.

MAIN OUTCOME MEASURES:

The functional ratings of individuals with normal cognition, MCI, or AD dementia who were evaluated at Alzheimer's Disease Centers and submitted to the National Alzheimer's Coordinating Center were assessed in accordance with the definition of "functional independence" allowed by the revised criteria. Pairwise demographic differences between the 3 diagnostic groups were tested using t tests for continuous variables and χ(2) for categorical variables.

RESULTS:

Almost all (99.8%) individuals currently diagnosed with very mild AD dementia and the large majority (92.7%) of those diagnosed with mild AD dementia could be reclassified as having MCI with the revised criteria, based on their level of impairment in the Clinical Dementia Rating domains for performance of instrumental activities of daily living in the community and at home. Large percentages of these individuals with AD dementia also meet the revised "functional independence" criterion for MCI as measured by the Functional Assessment Questionnaire.

CONCLUSIONS:

The categorical distinction between MCI and milder stages of AD dementia has been compromised by the revised criteria. The resulting diagnostic overlap supports the premise that "MCI due to AD" represents the earliest symptomatic stage of AD.

Arch Neurol. 2012 Feb 6. [Epub ahead of print]