Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease

Cerebrospinal fluid (CSF) and positron emission tomographic (PET) amyloid biomarkers have been proposed for the detection of Alzheimer disease (AD) pathology in living patients and for the tracking of longitudinal changes, but the relation between biomarkers needs further study. Indeed a study aimed at determining the association between CSF and PET amyloid biomarkers (cross-sectional and longitudinal measures) and compare the cutoffs for these measures has just been published:

Design, Setting, and Participants Longitudinal clinical cohort study from 2005 to 2014 including 820 participants with at least 1 florbetapir F-18 (hereafter referred to as simply florbetapir)–PET scan and at least 1 CSF β-amyloid 1-42 (Aβ1-42) sample obtained within 30 days of each other (501 participants had a second PET scan after 2 years, including 150 participants with CSF Aβ1-42 measurements). Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative database.

Main Outcomes and Measures Four different PET scans processing pipelines from 2 different laboratories were compared. The PET cutoff values were established using a mixture-modeling approach, and different mathematical models were applied to define the association between CSF and PET amyloid measures.

Results The values of the CSF Aβ1-42 samples and florbetapir-PET scans showed a nonlinear association (R2 = 0.48-0.66), with the strongest association for values in the middle range. The presence of a larger dynamic range of florbetapir-PET scan values in the higher range compared with the CSF Aβ1-42 plateau explained the differences in correlation with cognition (R2 = 0.36 and R2 = 0.25, respectively). The APOEgenotype significantly modified the association between both biomarkers. The PET cutoff values derived from an unsupervised classifier converged with previous PET cutoff values and the established CSF Aβ1-42 cutoff levels. There was no association between longitudinal Aβ1-42 levels and standardized uptake value ratios during follow-up.

Conclusions and Relevance The association between both biomarkers is limited to a middle range of values, is modified by the APOE genotype, and is absent for longitudinal changes; 4 different approaches in 2 different platforms converge on similar pathological Aβ cutoff levels; and different pipelines to process PET scans showed correlated but not identical results. Our findings suggest that both biomarkers measure different aspects of AD Aβ pathology.

Reference JAMA Neurol. Published online March 30, 2015. doi:10.1001/jamaneurol.2014.4829

Florbetaben PET imaging to detect amyloid plaques in Alzheimer disease: Phase 3 study

Background

Evaluation of brain β-amyloid by positron emission tomography (PET) imaging can assist in the diagnosis of Alzheimer disease (AD) and other dementias.

Methods

Open-label, nonrandomized, multicenter, phase 3 study to validate the 18F-labeled β-amyloid tracer florbetaben by comparing in vivo PET imaging with post-mortem histopathology.

Results

Brain images and tissue from 74 deceased subjects (of 216 trial participants) were analyzed. Forty-six of 47 neuritic β-amyloid-positive cases were read as PET positive, and 24 of 27 neuritic β-amyloid plaque-negative cases were read as PET negative (sensitivity 97.9% [95% confidence interval or CI 93.8–100%], specificity 88.9% [95% CI 77.0–100%]). In a subgroup, a regional tissue-scan matched analysis was performed. In areas known to strongly accumulate β-amyloid plaques, sensitivity and specificity were 82% to 90%, and 86% to 95%, respectively.

Conclusions

Florbetaben PET shows high sensitivity and specificity for the detection of histopathology-confirmed neuritic β-amyloid plaques and may thus be a valuable adjunct to clinical diagnosis, particularly for the exclusion of AD.

Trial registration

ClinicalTrials.govNCT01020838.

Predicting the risk of mild cognitive impairment

Objective: We sought to develop risk scores for the progression from cognitively normal (CN) to mild cognitive impairment (MCI).

Methods: We recruited into a longitudinal cohort study a randomly selected, population-based sample of Olmsted County, MN, residents, aged 70 to 89 years on October 1, 2004. At baseline and subsequent visits, participants were evaluated for demographic, clinical, and neuropsychological measures, and were classified as CN, MCI, or dementia. Using baseline demographic and clinical variables in proportional hazards models, we derived scores that predicted the risk of progressing from CN to MCI. We evaluated the ability of these risk scores to classify participants for MCI risk.

Results: Of 1,449 CN participants, 401 (27.7%) developed MCI. A basic model had a C statistic of 0.60 (0.58 for women, 0.62 for men); an augmented model resulted in a C statistic of 0.70 (0.69 for women, 0.71 for men). Both men and women in the highest vs lowest sex-specific quartiles of the augmented model's risk scores had an approximately 7-fold higher risk of developing MCI. Adding APOE ε4 carrier status improved the model (p = 0.002).

Conclusions: We have developed MCI risk scores using variables easily assessable in the clinical setting and that may be useful in routine patient care. Because of variability among populations, validation in independent samples is required. These models may be useful in identifying patients who might benefit from more expensive or invasive diagnostic testing, and can inform clinical trial design. Inclusion of biomarkers or other risk factors may further enhance the models.

Reference: Neurology 10.1212/WNL.0000000000001437

Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin

Objective: Authors investigated induction of α-secretase A disintegrin and metalloprotease 10 (ADAM10) by the synthetic retinoid acitretin (Neotigason; Actavis, München-Riem, Germany) in patients with mild to moderate Alzheimer disease (AD) via measurement of CSF content of α-secretase–derived amyloid precursor protein (APPs-α).

Methods: Twenty-one patients clinically diagnosed with mild to moderate AD received acitretin (30 mg per day) or placebo in a 4-week double-blind study. Primary endpoint was the difference of CSF APPs-α ratios calculated from the APPs-α levels after treatment and at baseline. We monitored safety and tolerability of the treatment. In addition, we assessed biomarkers such as β-amyloid 42 (Aβ₄₂) under treatment conditions.

Results: The acitretin group showed a significant increase in CSF APPs-α levels compared with the placebo group (difference 0.38, 95% confidence interval 0.03–0.72, p = 0.035) within this rather short treatment period. The synthetic retinoid acitretin was overall safe and well tolerated.

Conclusions: Our pilot study highlights that acitretin is able to enhance the nonamyloidogenic APP processing in human patients. Clinical consequences of this regulation should be investigated in larger and longer trials in patients with AD to evaluate acitretin's potential to serve as a novel therapeutic drug.

Classification of evidence: This study provides Class III evidence that in patients with AD, oral acitretin increases CSF APPs-α levels.

Reference: Neurology 10.1212/WNL.0000000000001017

Anatomical heterogeneity of Alzheimer disease

Objective: Because the signs associated with dementia due to Alzheimer disease (AD) can be heterogeneous, the goal of this study was to use 3-dimensional MRI to examine the various patterns of cortical atrophy that can be associated with dementia of AD type, and to investigate whether AD dementia can be categorized into anatomical subtypes.

Methods: High-resolution T1-weighted volumetric MRIs were taken of 152 patients in their earlier stages of AD dementia. The images were processed to measure cortical thickness, and hierarchical agglomerative cluster analysis was performed using Ward's clustering linkage. The identified clusters of patients were compared with an age- and sex-matched control group using a general linear model.

Results: There were several distinct patterns of cortical atrophy and the number of patterns varied according to the level of cluster analyses. At the 3-cluster level, patients were divided into (1) bilateral medial temporal–dominant atrophy subtype (n = 52, ∼34.2%), (2) parietal-dominant subtype (n = 28, ∼18.4%) in which the bilateral parietal lobes, the precuneus, along with bilateral dorsolateral frontal lobes, were atrophic, and (3) diffuse atrophy subtype (n = 72, ∼47.4%) in which nearly all association cortices revealed atrophy. These 3 subtypes also differed in their demographic and clinical features.

Conclusions: This cluster analysis of cortical thickness of the entire brain showed that AD dementia in the earlier stages can be categorized into various anatomical subtypes, with distinct clinical features.

Reference: Neurology 10.1212/WNL.0000000000001003

The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey

The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it “always/frequently”) followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as “moderate”. Seventy-nine percent of responders felt “very/extremely” comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.

DOI: http://dx.doi.org/10.1016/j.jalz.2014.06.006

Diagnostic impact of CSF biomarkers for Alzheimer's disease in a tertiary memory clinic

Background

We aimed to assess the impact of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease on decision making and patient management in a tertiary memory clinic.

Methods

We included all patients, for 1 year, visiting the VUmc Alzheimer Center for cognitive screening. Neurologists completed questionnaires before and after CSF disclosure. We assessed the change of diagnosis, diagnostic confidence, and impact on patient management.

Results

A total of 438 patients (age 63 ± 8 years, 39% women) were included, of whom 351 (80%) underwent lumbar puncture. After the disclosure of CSF 23/351 diagnoses (7%) were changed. Diagnostic confidence increased from 84% to 89% (P < .001). There were consequences for management in 44/351 patients (13%) with CSF, and 13/87 patients (15%) because of unavailable CSF. There was no effect of age on these results.

Conclusions

CSF biomarkers aid clinicians with decision making during diagnostic work-up of cognitive disorders. This study may be useful for developing guidelines for the implementation of CSF biomarkers in daily practice.

DOI: http://dx.doi.org/10.1016/j.jalz.2014.05.1753