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

FDA Approves Third Amyloid PET Tracer for Alzheimer's

The US Food and Drug Administration (FDA) has approved a third agent for imaging β-amyloid in the setting of Alzheimer's disease (AD), florbetaben F18 injection (Neuraceq, Piramal Imaging).

Florbetaben is indicated for positron emission tomography (PET) of the brain to estimate β-amyloid neuritic plaque density in adults with cognitive impairment who are being evaluated for AD and other causes of cognitive decline. It was recently also approved in Europe.

Two other PET imaging tracers, florbetapir (Amyvid, Eli Lilly and Company) and flutemetamol (Vizamyl, GE Healthcare), were approved previously by the FDA in 2012 and 2013, respectively.

Plasma biomarkers could predict Alzheimer's before it starts

A simple blood test has the potential to predict whether a healthy person will develop symptoms of dementia within two or three years. If larger studies uphold the results, the test could fill a major gap in strategies to combat brain degeneration, which is thought to show symptoms only at a stage when it too late to treat effectively.

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Amyloid imaging

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