March 14, 2016

Alzheimer’s & Dementia: A Journal of the Alzheimer’s Association.




 

Alzheimer’s & Dementia: A Journal of the Alzheimer’s Association. Volume 12, Issue 1, January 2016

 


Kunkle, et al. p2-10.

 

Abstract

Introduction
Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found.

 

Methods
We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles.

 

Results
Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2–11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2–14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases.

 

Discussion
Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.

 

 


Nogueira, et al. p11-20

 

Abstract

Introduction

The effects related to endogenous mechanical energy in Alzheimer's disease (AD) pathology have been widely overlooked. With the support of available data from literature and mathematical arguments, we hypothesize that brain atrophy in AD could be co-driven by the cumulative impact of the pressure within brain tissues.

Methods

Brain volumetric and physical data in AD and normal aging (NA) were extracted from the literature. Average brain shrinkage and axial deformations were evaluated mathematically. Mechanical stress equivalents related to brain shrinkage were calculated using a conservation law derived from fluid and solid mechanics.

Results

Pressure equivalents of 5.92 and 3.43 mm Hg were estimated in AD and in NA, respectively.

Discussion

The calculated increments of brain mechanical stress in AD, which could be impacted by marked dampening of arterial pulse waves, may point to the need to expand the focus on the mechanical processes underpinning pathologic aging of the brain.

 


Chen, et al. p 21-33

 

Abstract

Introduction

Consistent evidence linking habitual sleep duration with risks of mild cognitive impairment (MCI) and dementia is lacking.

Methods

We conducted a prospective study on 7444 community-dwelling women (aged 65–80 y) with self-reported sleep duration, within the Women's Health Initiative Memory Study in 1995–2008. Incident MCI/dementia cases were ascertained by validated protocols. Cox models were used to adjust for multiple sociodemographic and lifestyle factors, depression, cardiovascular disease (CVD), and other clinical characteristics.

Results

We found a statistically significant (P = .03) V-shaped association with a higher MCI/dementia risk in women with either short (≤6 hours/night) or long (≥8 hours/night) sleep duration (vs. 7 hours/night). The multicovariate-adjusted hazard for MCI/dementia was increased by 36% in short sleepers irrespective of CVD, and by 35% in long sleepers without CVD. A similar V-shaped association was found with cognitive decline.

Discussion

In older women, habitual sleep duration predicts the future risk for cognitive impairments including dementia, independent of vascular risk factors.

 


Tweedie, et al. p 34-48

 

Abstract

Introduction
Blast traumatic brain injury (B-TBI) affects military and civilian personnel. Presently, there are no approved drugs for blast brain injury.

 

Methods
Exendin-4 (Ex-4), administered subcutaneously, was evaluated as a pretreatment (48 hours) and postinjury treatment (2 hours) on neurodegeneration, behaviors, and gene expressions in a murine open field model of blast injury.

 

Results
B-TBI induced neurodegeneration, changes in cognition, and genes expressions linked to dementia disorders. Ex-4, administered preinjury or postinjury, ameliorated B-TBI–induced neurodegeneration at 72 hours, memory deficits from days 7–14, and attenuated genes regulated by blast at day 14 postinjury.

 

Discussion
The present data suggest shared pathologic processes between concussive and B-TBI, with end points amenable to beneficial therapeutic manipulation by Ex-4. B-TBI–induced dementia-related gene pathways and cognitive deficits in mice somewhat parallel epidemiologic studies of Barnes et al. who identified a greater risk in US military veterans who experienced diverse TBIs, for dementia in later life.

 


Arthur W. Toga p49-54

 

Abstract

Introduction
The Global Alzheimer's Association Interactive Network (GAAIN) is consolidating the efforts of independent Alzheimer's disease data repositories around the world with the goals of revealing more insights into the causes of Alzheimer's disease, improving treatments, and designing preventative measures that delay the onset of physical symptoms.

 

Methods
We developed a system for federating these repositories that is reliant on the tenets that (1) its participants require incentives to join, (2) joining the network is not disruptive to existing repository systems, and (3) the data ownership rights of its members are protected.

 

Results
We are currently in various phases of recruitment with over 55 data repositories in North America, Europe, Asia, and Australia and can presently query >250,000 subjects using GAAIN's search interfaces.

 

Discussion
GAAIN's data sharing philosophy, which guided our architectural choices, is conducive to motivating membership in a voluntary data sharing network.

 


Pannee, et al. p55-59.

 

Abstract

Introduction
Cerebrospinal fluid (CSF) amyloid-β 1–42 (Aβ42) is an important biomarker for Alzheimer's disease, both in diagnostics and to monitor disease-modifying therapies. However, there is a great need for standardization of methods used for quantification. To overcome problems associated with immunoassays, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a critical orthogonal alternative.

 

Methods
We compared results for CSF Aβ42 quantification in a round robin study performed in four laboratories using similar sample preparation methods and LC-MS instrumentation.

 

Results
The LC-MS results showed excellent correlation between laboratories (r2 >0.98), high analytical precision, and good correlation with enzyme-linked immunosorbent assay (r2 >0.85). The use of a common reference sample further decreased interlaboratory variation.

 

Discussion
Our results indicate that LC-MS is suitable for absolute quantification of Aβ42 in CSF and highlight the importance of developing a certified reference material.

 

 


Gauthier, et al. p60–64.

 

Abstract
The success rate of the pharmaceutical research and development (R&D) for dementia drugs has been abysmally low, in the last two decades. Also low has been the number of pipeline drugs in development, compared to other therapy areas. However, the rationale of early terminations has not been reported in the majority of trials. These are key findings of the recently published pharmaceutical pipeline analysis by the UK-based Office of Health Economics (OHE). Our understanding of main challenges include (1) the significant gaps of knowledge in the nosology and complexity of the underpinning biological mechanisms of the commonest, not familial, forms of late onset dementias; (2) low signal-to-noise ratio, notwithstanding the lack of validated biomarkers as entry and/or end-point criteria; (3) recruitment and retention, particularly in the asymptomatic and early disease stages. A number of current and future strategies aimed at ameliorating drug development are outlined and discussed.

 

 


Hubin, et al. p65-74.e1.

 

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that involves a plethora of molecular pathways. In the context of therapeutic treatment and biomarker profiling, the amyloid-beta (Aβ) peptide constitutes an interesting research avenue that involves interactions within a complex mixture of Aβ alloforms and other disease-modifying factors. Here, we explore the potential of an ecosystem paradigm as a novel way to consider AD and Aβ dynamics in particular. We discuss the example that the complexity of the Aβ network not only exhibits interesting parallels with the functioning of complex systems such as ecosystems but that this analogy can also provide novel insights into the neurobiological phenomena in AD and serve as a communication tool. We propose that combining network medicine with general ecosystem management principles could be a new and holistic approach to understand AD pathology and design novel therapies.

 


Gordon, et al. p75-84.

 

Abstract

Introduction

As drug development research efforts move toward studying patients earlier in the course of Alzheimer's disease (AD), it is important to incorporate the patient's perspective into measurement of outcomes.

Methods

This article summarizes the qualitative work of the Patient-Reported Outcome Consortium's Cognition Working Group in the development of a new self-reported outcome measure in persons with mild cognitive impairment (MCI) due to suspected AD, herein referred to as MCI.

Results

The draft measure captures the patient's voice for two functional domains, complex activities of daily living and interpersonal functioning.

Discussion

This work represents a series of initial steps in the development of this rating scale. The next steps are to conduct psychometric analysis and evaluate the role of insight.

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