TDP-43 pathology and memory impairment in elders without pathologic diagnoses of AD or FTLD

Objective:To investigate the association of TAR DNA-binding protein 43 (TDP-43) pathology with memory, other cognitive domains, and dementia in community-dwelling elders without pathologic diagnoses of Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD).Methods:Of 1,058 autopsied participants, 343 (32.4%) did not have pathologic diagnoses of AD or FTLD. Diagnosis of dementia was based on clinical evaluation and cognitive performance tests, which were used to create summary measures of global cognition and of 5 cognitive domains. TDP-43 pathology evaluated in 6 brain regions by immunohistochemistry was converted into a summary measure of TDP-43 severity.Results:Of 343 participants, 135 (39.4%) had TDP-43 pathology with a mean TDP-43 severity score of 0.394 (SD 0.490). TDP-43 inclusions were confined to the amygdala (stage 1) in 43.7% of participants, 40% showed additional involvement of the hippocampus or entorhinal cortex (stages 2), while fewer (16.3%) showed additional TDP-43 pathology in the temporal and frontal cortices (stage 3). Severity of TDP-43 pathology was independently related to lower function in global cognition and episodic and semantic memory while increased odds of dementia was only a trend. When participants with hippocampal sclerosis (HS) were excluded from the models, TDP-43 pathology remained associated with lower episodic memory but relationships with global cognition, semantic memory, and dementia were attenuated.Conclusions:TDP-43 pathology in elders, without pathologic diagnoses of AD or FTLD, is common and independently associated with lower function in episodic memory, while its associations with global cognitive impairment and dementia are difficult to separate from HS.

A Strongly Interacting Dynamic Particle Swarm Optimization Method

A novel dynamic interacting particle swarm optimization algorithm (DYN-PSO) is proposed. The algorithm can be considered to be the synthesis of two established trajectory methods for unconstrained minimization. In the new method, the minimization of a function is achieved through the dynamic motion of a strongly interacting particle swarm, where each particle in the swarm is simultaneously attracted by all other particles located at positions of lower function value. The force of attraction experienced by a particle at higher function value due to a particle at a lower function value is equal to the difference between the respective function-values divided by their stochastically perturbed position difference. The resultant motion of the particles under the influence of the attracting forces is computed by solving the associated equations of motion numerically. An energy dissipation strategy is applied to each particle. The specific chosen force law and the dissipation strategy result in the rapid collapse (convergence) of the swarm to a stationary point. Numerical results show that, in comparison to the standard particle swarm algorithm, the proposed DYN-PSO algorithm is promising.

Identification of ADRA2A Polymorphisms Related to Shear-Mediated Platelet Function by the PFA-100® System.

[Background] α 2A adrenergic receptor (ADRA2A) on platelets interacts with epinephrine, which has a key role in regulating platelet functions. There is familial clustering of inter-individual variations in the epinephrine-induced platelet aggregation, the molecular basis of which, however, has not been fully understood. In this study, we screened the sequence variations in the transcriptional region of ADRA2A gene and analyzed the relationship between the two common polymorphisms and platelet function using collagen/epinephrine (CEPI) cartridge in the platelet function analyzer (PFA)-100® system. [Methods and Results] Written informed consent was obtained from all study subjects who were genetically unrelated healthy Japanese males (n=255). Of the 255 subjects, an initial screening for the sequence variation(s) in the ADRA2A transcriptional region was performed on 44 subjects enrolled in 2003. Subsequently, relationship between ADRA2A polymorphisms and platelet function was investigated in 211 subjects enrolled between 2004 and 2005. In the screening, we observed 16 single nucleotide polymorphisms (SNPs) including 5 novel variations. We next examined the association between the ADRA2A polymorphisms and epinephrine-mediated platelet function using the PFA-100® system under high shear conditions (5000–6000/sec). According to the pilot study on the 16 SNPs, we focused on 1780A/G and 2732A/G (the first nucleotide of the open reading frame is nt#1, which corresponds to nt#31586326 of the GenBank NT_030059). We measured platelet function, as assessed by closure time (CT) using CEPI cartridge. A longer CEPI-CT indicates lower platelet function in the interaction with collagen and epinephrine. Because the manufacturer’s instructions for the PFA-100® report a mean CEPI-CT value of 132 s, study subjects were divided in two groups: a higher function group with a CEPI-CT < 132 s (n=90) and a lower function group with a CEPI-CT ≥ 132 s (n=121). The frequency of the 1780GG genotype in the lower function group was significantly higher than that in the higher function group (p=0.0478) whereas no association between the CEPI-CT and the 2372A/G polymorphism was observed (p=0.1164). We also observed the effect of the combination of 1780GG+2372AA genotypes for shorter CT (p=0.0319). A multiple logistic regression model to adjust the reported confounding factors (VWF: RCo, platelet count, and hematocrit) revealed an adjusted odds ratio of 2.10 (p=0.0274) for the genotypic combination or 1.82 (p=0.0757) for the 1780A/G alone. Plasma VWF:RCo level was also an independent predictor for CEPI-CT. These observations suggested the enhanced effect of the genotypic combination as compared with the 1780A/G alone. [Conclusion] Of the 16 sequence variations of the transcriptional region of the ADRA2A gene, the combination of the 1780A/G and 2372A/G polymorphism was associated with collagen/epinephrine-mediated platelet function by PFA-100® system.

Misspecified change-point estimation problem for a Poisson process

Consider an inhomogeneous Poisson process X on [0, T] whose unknown intensity function ‘switches' from a lower function g∗ to an upper function h∗ at some unknown point θ∗. What is known are continuous bounding functions g and h such that g∗(t) ≤ g(t) ≤ h(t) ≤ h∗(t) for 0 ≤ t ≤ T. It is shown that on the basis of n observations of the process X the maximum likelihood estimate of θ∗ is consistent for n →∞, and also that converges in law and in pth moment to limits described in terms of the unknown functions g∗ and h∗.

Misspecified change-point estimation problem for a Poisson process

Consider an inhomogeneous Poisson process X on [0, T] whose unknown intensity function ‘switches' from a lower function g∗ to an upper function h∗ at some unknown point θ ∗. What is known are continuous bounding functions g and h such that g∗ (t) ≤ g(t) ≤ h(t) ≤ h∗ (t) for 0 ≤ t ≤ T. It is shown that on the basis of n observations of the process X the maximum likelihood estimate of θ ∗ is consistent for n →∞, and also that converges in law and in pth moment to limits described in terms of the unknown functions g∗ and h ∗.