Current Alzheimer Research (v.10, #9)

Military Risk Factors for Cognitive Decline, Dementia and Alzheimerµs Disease by Dallas P. Veitch, Karl E. Friedl, Michael W. Weiner (907-930).
Delayed neurological health consequences of environmental exposures during military service have been generallyunderappreciated. The rapidly expanding understanding of Alzheimer's disease (AD) pathogenesis now makes itpossible to quantitate some of the likely long-term health risks associated with military service. Military risk factors forAD include both factors elevated in military personnel such as tobacco use, traumatic brain injury (TBI), depression, andpost-traumatic stress disorder (PTSD) and other nonspecific risk factors for AD including, vascular risk factors such asobesity and obesity-related diseases (e.g., metabolic syndrome), education and physical fitness. The degree of combat exposure,Vietnam era Agent Orange exposure and Gulf War Illness may also influence risk for AD. Using available data onthe association of AD and specific exposures and risk factors, the authors have conservatively estimated 423,000 newcases of AD in veterans by 2020, including 140,000 excess cases associated with specific military exposures. The cost associatedwith these excess cases is approximately $5.8 billion to $7.8 billion. Mitigation of the potential impact of militaryexposures on the cognitive function of veterans and management of modifiable risk factors through specifically designedprograms will be instrumental in minimizing the impact of AD in veterans in the future decades.

Pupil Response Biomarkers for Early Detection and Monitoring of Alzheimerµs Disease by Shaun Frost, Yogesan Kanagasingam, Hamid Sohrabi, Pierrick Bourgeat, Victor Villemagne, Christopher C. Rowe, S. Lance Macaulay, Cassandra Szoeke, Kathryn A. Ellis, David Ames, Colin L. Masters, Stephanie Rainey-Smith, Ralph N. Martins, AIBL Research Group (931-939).
Introduction A screening process that could provide early and accurate diagnosis or prognosis for Alzheimer'sdisease (AD) would enable earlier intervention, and enable current and future treatments to be more effective. Ocular pathologyand changes to vision and ocular function are being investigated for early detection and monitoring of AD. Objective To explore the relationship between pupil flash response (PFR) parameters, AD and brain amyloid plaque burden. Methods NineteenADandseventyhealthy control (HC) participants were recruited from the Australian Imaging, Biomarkersand Lifestyle (AIBL) Flagship Study of Ageing. Thepotential correlations betweenPFRparameters and1) AD and 2)brain amyloid plaque burden in the HC group (as a pre-clinical feature of AD), were investigated in this study. Results Our results demonstratestatistically significant relationships between PFR parameters, neocortical plaque burden and AD.A logistical model combining PFR parameters provided AD-classification performance with sensitivity 84.1%, specificity78.3% and area under the curve 89.6%. Furthermore, some of the AD specific PFR parameters were also associated withneocorticalplaque burden in pre-clinical AD. Conclusions These PFR changes show potential as an adjunct for noninvasive,cost-effective screening for pre-clinical AD.

Sensitivity of Different MRI-Techniques to Assess Gray Matter Atrophy Patterns in Alzheimerµs Disease is Region-Specific by L. Clerx, H.I.L. Jacobs, S. Burgmans, E.H.B.M. Gronenschild, H.B.M. Uylings, C. Echávarri, P. J. Visser, F. R.J. Verhey, P. Aalten (940-951).
The present study compares four different structural magnetic resonance imaging techniques used to measuregray matter (GM) atrophy in Alzheimer's disease (AD): manual and automated volumetry, cortical thickness (CT) andvoxel-based morphometry (VBM). These techniques are used interchangeably in AD research and thus far it is unclearwhich technique is superior in detecting abnormalities early in the disease process. 18 healthy participants without anymemory impairment, 18 patients with MCI, and 17 patients with mild AD were included and between-group differenceswere investigated in AD signature regions (areas in the prefrontal cortex (PFC), medial temporal lobe (MTL) and posteriorparietal cortex (PPC)). Both manual volumetric measurements and VBM were able to detect GM atrophy in the earlystages (differentiation controls and MCI), mainly in the MTL. In the early phase, automated volumetric measurementsshowed GM differences in the PPC but not in the MTL. In our sample, CT measurements were not sensitive for group differencesin the early stages. PFC regions showed abnormalities in the later stages (controls vs AD) when manual volumetricmeasurements or VBM are employed. Manual volumetric measurements together with VBM are preferred techniquesfor assessing GM differences showing abnormalities in most of the investigated regions, with a predominance of the MTLin the early phase. Automated FreeSurfer volumetric measurements show similar performances in the early phase, displayinggroup differences in the PPC but not in MTL regions. Measurements of CT are less sensitive in the MCI stage andits sensitivity is restricted to the MTL and PPC regions in later stages of the disease (AD).

Reliability of the Alzheimerµs Disease Assessment Scale (ADAS-Cog) in longitudinal Studies by Anzalee Khan, Christian Yavorsky, Guillermo DiClemente, Mark Opler, Stacy Liechti, Brian Rothman, Sofija Jovic (952-963).
Background: Considering the scarcity of longitudinal assessments of reliability, there is need for a more preciseunderstanding of cognitive decline in Alzheimer's Disease (AD). The primary goal was to assess longitudinal changes ininter-rater reliability, test retest reliability and internal consistency of scores of the ADAS-Cog.Methods: 2,618 AD subjects were enrolled in seven randomized, double-blind, placebo-controlled, multicenter-trials from1986 to 2009. Reliability, internal-consistency and cross-sectional analysis of ADAS-Cog and MMSE across seven visitswere examined.Results: Intra-class correlation (ICC) for ADAS-Cog was moderate to high supporting their reliability. Absolute AgreementICCs 0.392 (Visit-7) to 0.806 (Visit-2) showed a progressive decrease in correlations across time. Item analysis revealeda decrease in item correlations, with the lowest correlations for Visit 7 for Commands (ICC=0.148), Comprehension(ICC=0.092), Spoken Language (ICC=0.044).Discussion: Suitable assessment of AD treatments is maintained through accurate measurement of clinically significantoutcomes. Targeted rater education ADAS-Cog items over-time can improve ability to administer and score the scale.

Correlations Between Cerebellar and Brain Volumes, Cognitive Impairments, ApoE Levels, and APOE Genotypes in Patients with AD and MCI by Wanda Lojkowska, Grzegorz Witkowski, Malgorzata Bednarska-Makaruk, Hanna Wehr, Halina Sienkiewicz-Jarosz, Alla Graban, Anna Bochynska, Anna Wisniewska, Magdalena Gugala, Ksenia Slawinska, Beata Sawicka, Renata Poniatowska, Danuta Ryglewicz (964-972).
Due to the increasing incidence of Alzheimer's disease (AD), many studies have aimed to improve its diagnosis.Particular attention has been focused on measuring volumes of brain structures. Only few studies have investigatedwhetherthe cerebellar volume changes with the stage of dementia. It is controversial whether the serum apolipoprotein E(ApoE) level is an appropriate AD marker. This study was designed to clarify the significance of both cerebellar volumemeasurements and ApoE level measurements as markers of neurodegenerative changes.This study included 55 subjects with AD, 30 subjects with mild cognitive impairments (MCI), and a control group with 30subjects. We measured the brain, cerebellum, and brain stem volumes with magnetic resonance imaging (MRI). We determinedserum ApoE levels, APOE genotypes, and neuropsychological test scores.In the control group, we found that ApoE levels were significantly higher for subjects with the APOE 2/3 genotype thanthose with the 4/4 genotype. This finding may indicate that ApoE plays a protective role against AD development in subjectswith the APOE 2/3 genotype. ApoE levels were not significantly different in patients with AD and MCI. No correlationswere found between serum ApoE levels and Mini-Mental State Examination (MMSE) scores or the volumes of brainstructures.This study could not confirm the appropriateness of the cerebellum volume as an early AD marker. Correlations werefound between cerebellar volume, brain volume, and the MMSE scores.

Plasma Clusterin Levels and the rs11136000 Genotype in Individuals with Mild Cognitive Impairment and Alzheimerµs Disease by Gemma M. Mullan, Jane McEneny, Marc Fuchs, Cyril McMaster, Stephen Todd, Bernadette McGuinness, Mark Henry, A. Peter Passmore, Ian S Young, Janet A. Johnston (973-978).
Aim: Substantial evidence links atherosclerosis and Alzheimer's disease (AD). Apolipoproteins, such asapolipoprotein E, have a causal relationship with both diseases. The rs11136000 SNP within the CLU gene, whichencodes clusterin (apolipoprotein J), is also associated with increased AD risk. The aim of this study was to investigate therelationship between plasma clusterin and the rs11136000 genotype in mild cognitive impairment (MCI) and AD.Methods: Plasma and DNA samples were collected from control, MCI and AD subjects (n=142, 111, 154, respectively).Plasma clusterin was determined by ELISA and DNA samples were genotyped for rs11136000 by TaqMan assay.Results: Plasma clusterin levels were higher in MCI and AD subjects vs. controls (222.3±61.3 and 193.6±58.2 vs.178.6±52.3 g/ml, respectively; p<0.001 for both comparisons), and in MCI vs. AD (p<0.05). Plasma clusterin was notinfluenced by genotype in the MCI and AD subjects, although in control subjects plasma clusterin was lower in the TT vs.TC genotypes (157.6±53.4 vs. 188.6±30.5 g/ml; p<0.05).Conclusion: This study examined control, MCI and AD subjects, identifying for the first time that plasma clusterin levelswere influenced, not only by the presence of AD, but also the transitional stage of MCI, while rs11136000 genotype onlyinfluenced plasma clusterin levels in the control group. The increase in plasma clusterin in MCI and AD subjects may occurin response to the disease process and would be predicted to increase binding capacity for amyloid-beta peptides inplasma, enhancing their removal from the brain.

Serum β-Amyloid Peptide Levels Spike in the Early Stage of Alzheimer- Like Plaque Pathology in an APP/PS1 Double Transgenic Mouse Model by Jue He, Jin-Ping Qiao, Shenghua Zhu, Mengzhou Xue, Wenwu Chen, Xinchun Wang, Adrien Tempier, Qingjun Huang, Jiming Kong, Xin-Min Li (979-986).
Serum levels of β-amyloid (A ) peptides may represent an early biomarker in the diagnosis of Alzheimer's disease(AD). In the present study, we investigated the temporal kinetic changes in the levels of serum Aβ 1-42 and 40 in anamyloid precursor protein (APP)/presenilin (PS)1 double transgenic mouse model of AD. Serum Aβ peptide levels in 2-,3-, 6-, 9- and 18-month old, and liver Aβ 1-40 level in 6-month old mice were measured using enzyme-linked immunosorbentassay (ELISA) kits. Results revealed that serum Aβ levels peaked in 3-month old transgenic mice, and the Aβ level in non-transgenic and transgenic mice is comparable in liver. Compared to the 6-month old transgenic mice, Congored staining showed that the 3-month old transgenic mice had minimum brain Aβ plaques, corresponding to the earlystage of Alzheimer-like plaque pathology, and confocal microscope images showed that the deposition of Aβ in theircerebral vessels was minimal. Furthermore, results of the water maze test, showed that memory was normal for the 3-month old transgenic mice when compared to age-matched non-transgenic mice. These results suggest that serum Aβ peptidelevels may be peaked during the early stage of AD. Monitoring serum Aβ peptide levels in the potential AD populationmay provide an early diagnosis of AD prior to the appearance of clinical symptoms.

Neurodegeneration is induced by tryptamine, a human diet constituent, which easily crosses the blood/brainbarrier. Tryptamine neurotoxicity, caused by tryptophanyl-tRNA synthetase (TrpRS) inhibition and downregulation leadsto tryptophanyl-tRNA deficiency and synthesis of aberrant proteins. We identified axonal defects in hippocampus of tryptamine-treated mice similar to those observed in human brain of patients with Alzheimer's disease, multiple sclerosis andepilepsy using anti-TrpRS site-directed antibodies. The axonal defects are characterized by swellings that accumulate abnormalamounts of helical filaments and amyloid. Tryptamine produced a decreased density of somatic mitochondria concomitantwith neuronal loss in mouse hippocampus. In addition, tryptamine evoked accumulation and clustering of smallmitochondria in mouse hippocampus causing axonal swellings. Similarly, mitochondrial fission, fusion and clusteringwere revealed in human neuronal cells after tryptamine administration. Moreover the tryptamine-induced mitochondrialneuropathology includes electron-dense deposits comprising helical fibrils, cristae disruption, cristolysis, mitochondrialswelling and mitochondria-derived vesicles. TrpRS+ helical filamentous tangles formed in both neuronal and kidney cellsfollowing tryptamine treatment suggest a tryptamine broad cytotoxic repertoire in damaging vital organs. Tryptamine elicitedvesicularization of inner and outer mitochondrial membranes, axonal and cell membranes. Ultrastructurally, fragmentationof swollen degenerated mitochondria, small mitochondria clustering and neurofibrillary tangles are associated withaxonal membrane protrusions attributed as neuritic swellings at a lower magnification. TrpRS+ axonal swellings associatedwith neuropathology of patients and tryptamine-treated human cells suggest that under toxic concentrations, tryptamineis implicated as a causative agent in neurodegeneration resembling that defining a number of human diseases.

Inhalational Anesthetic Sevoflurane Rescues Retina Function in Alzheimerµs Disease Transgenic Drosophila by Chia-Wen Chen, Wei-Yong Lin, Kuen-Bao Chen, Yih-Shyuan Wu, Yu-Cheng Kuo, Hsin-Ping Liu, Chi-Yuan Li (1005-1014).
Alzheimer's disease (AD) is a neurodegenerative disease that is a great public health problem worldwide. Thecause and mechanism of AD are not well understood. Inhalational anesthetics have been suggested to induce neurotoxicity,leading to memory deficits and the progression of AD. However, recent data have shown that inhalational anestheticsmay protect against neurotoxicity and are not associated with an increased risk of AD. We used a Drosophila model to directlyinvestigate the neurologic effects of the inhalational anesthetic sevoflurane on AD. Five- to six-day-old control andAD-transgenic flies were exposed to 2.1% or 3% sevoflurane 4 and 16 times for 1 hour each time. Electroretinograms(ERG), retinal immunohistochemistry, climbing ability, and survival were analyzed after sevoflurane treatment. The datawere evaluated using Student's t-test or a one-way ANOVA with a supplementary Fisher's LSD (Least Significant Difference)test. Statistical significance was set at p<0.05. The ΔERG, climbing ability, and survival were lower in ADtransgenicflies. Exposure to 2.1% sevoflurane 4 and 16 times and to 3% sevoflurane 16 times rescued the ΔERG in ADtransgenicflies. Sevoflurane exposure did not attenuate the climbing ability or survival of control and AD-transgenic flies.The inhalational anesthetic sevoflurane might not have exerted neurotoxic effects on control and AD-transgenic flies; infact, sevoflurane might confer selective neuroprotection on the retinal function of AD-transgenic flies. These results suggestthe need for future studies to determine the potential effects of anesthetics on AD-associated neuroprotection or neurotoxicity.