Current Alzheimer Research (v.11, #4)

Associations of Cerebrovascular and Alzheimerµs Disease Pathology with Brain Atrophy by Howard A. Crystal, Julie A. Schneider, David A. Bennett, Sue Leurgans, Steven R. Levine (309-316).
Cortical atrophy and brain vascular disease are both associated with dementia, but there are only limited pathologicaldata on the association of brain vascular disease with cortical atrophy. We studied pathological material from theRush Memory and Aging Project (MAP, N = 445). Cortical and hippocampal atrophy, and atherosclerosis at the circle ofWillis (large vessel disease, LVD) and arteriolosclerosis (small vessel disease, SVD) were rated by neuropathologists unawareof this study's hypothesis. Quantitative measures of Alzheimer's disease (AD) pathology, specifically neuronalneurofibrillary tangles (NFT) and amyloid-beta (A β) burden, were also obtained. Chronic micro and macroscopic infarctswere noted. In ordinal logistic regression models that included age at death, sex, apoE genotype, statin-use, Aβ and NFT,more severe LVD was significantly associated with more severe cortical and hippocampal atrophy. The odds ratio for theassociation of the most severe LVD (compared to the least) with cortical atrophy was 2.7 (CI: 1.5-4.7) p = 0.001; for hippocampalatrophy the odds ratio was 2.8 (CI: 1.5-5.2), p = 0.001. The association of SVD with atrophy did not follow aconsistent pattern. Neither macroscopic infarcts nor microscopic infarcts were associated with cortical or hippocampal atrophy(p's > 0.15). Tangle density was associated with cortical (p = 0.014) and hippocampal atrophy (p < 0.001). In contrast,amyloid burden was associated with less cortical (p = 0.02) or hippocampal (p = 0.002) atrophy. In this largeautopsy study LVD was associated with cortical and hippocampal atrophy. The relationship between SVD and atrophy requiresfurther study.

Accumulation of Intraneuronal Amyloid-β is Common in Normal Brain by Jeffrey A. Blair, Sandra L. Siedlak, Julie A. Wolfram, Akihiko Nunomura, Rudy J. Castellani, Sergio T. Ferreira, William L. Klein, Yang Wang, Gemma Casadesus, Mark A. Smith, George Perry, Xiongwei Zhu, Hyoung-gon Lee (317-324).
Intraneuronal amyloid-β (iAβ) accumulation has been demonstrated in Alzheimer disease (AD). Although extracellularamyloid plaques composed primarily of aggregated amyloid-β are one of the main pathological features of AD,functional characterization of iAβ is still lacking. In this study, we identified the normal distribution of iAβ through ananalysis of hippocampal sections from a series of over 90 subjects with diverse antemortem clinical findings. In additionto AD cases, iAβ in pyramidal neurons was readily and reproducibly demonstrated in the majority of control cases. Similarfindings for controls were made across all ages, spanning from infants to the elderly. There was no correlation of iAβbetween gender, postmortem interval, or age. While the possible pathophysiological significance of iAβ accumulation inAD remains to be elucidated, careful examination of iAβ found in the normal brain may be informative for determiningthe biological role of iAβ and how this function changes during disease. Current findings support a physiological role foriAβ in neuronal function over the entire lifespan.

Amyloid beta (Aβ ), especially Aβ oligomers, is important in early Alzheimer's disease (AD) pathogenesis.AD-associated inflammation has generally been considered as a secondary response to the pathological lesions evoked byAβ oligomers in the early stage of pathogenesis. We studied the levels of plasma Aβ monomers, A β oligomers, and solubletumor necrosis factor α receptors (sTNFRs) in 120 controls, 32 amnestic mild cognitive impairment (aMCI) patients,and 90 mild AD patients. The plasma A β monomer, oligomer and sTNFR levels were measured by ELISA. We observedthat the Aβ oligomer levels in mild AD patients were significantly higher than those in aMCI (200.8±83.8 versus93.9±23.3, P<0.05) and healthy subjects (200.8±83.8 versus 70.0±60.9, P<0.05). The sTNFR levels in the plasma ofaMCI and mild AD patients were significantly higher than the levels of control subjects. Moreover, the levels of bothsTNFR1 and sTNFR2 were significantly correlated with A β oligomer levels in aMCI (sTNFR1r= 0.376, P= 0.034;sTNFR2r= 0.367, P= 0.039) and mild AD patients (sTNFR1r= 0.471, P< 0.001; sTNFR2 r= 0.407, P< 0.001).More importantly, changes in A β oligomer and sTNFR levels accurately differentiated mild AD patients from control subjects,supporting these levels might be potential diagnostic biomarkers for aMCI and AD.

RCAN1 Increases Aβ Generation by Promoting N-glycosylation via Oligosaccharyltransferase by Tan Wang, Heng Liu, Yun Wang, Changqing Liu, Xiulian Sun (332-339).
Glycosylation is one of the major post-translational modifications, required for proper folding and functions ofglycoproteins. N-glycosylation in ER is mediated by oligosaccharyltransferase (OST), an enzyme complex transferringpreassembled oligosaccharide to asparagine residues of nascent polypeptide chain. Our study here indicates that regulatorof calcineurin 1 (RCAN1) can enhance N-glycosylation in ER, therefore elevates the activities of β - and γ-secretase andmarkedly increases A β production. We found that RCAN1 stabilizes OST by interacting with OST component ribophorinI(RPN I). RCAN1 enhanced glycosylation of membrane proteins and glycosylation sequon GNSTVT, but has no effect ontransferrin whose glycosylation was only affected by OST catalytic subunit STT3A, suggesting the effect of RCAN1 isassociated with RPN I in facilitating substrate delivery. Our previous studies have shown that RCAN1 was increased inAD brains and RCAN1 overexpression induced neuronal apoptosis. Here our study showed that RCAN1 further contributesto AD pathogenesis by increasing N-glycosylation and Aβ production.

CSF Ubiquitin As a Specific Biomarker in Alzheimer's Disease by Ramesh J. Kandimalla, R. Anand, R. Veeramanikandan, Willayat Yousuf Wani, Sudesh Prabhakar, Vinod K. Grover, Neerja Bharadwaj, Kajal Jain, Kiran Dip Gill (340-348).
Alzheimer's disease (AD) is the most common cause of dementia worldwide. Although, many putative biomarkersare reported for AD, only a few have been validated in the clinical setting. Ubiquitin levels increase in cerebrospinalfluid (CSF) of patients with AD, but its diagnostic value is not clear. In this present study we evaluate the performanceof ubiquitin as a diagnostic marker and deduce a statistical association with disease pathology in AD. Ubiquitin levelswere estimated in subjects with AD, other forms of dementias, neurological disorders and healthy age matched population.The levels of ubiquitin were significantly higher in subjects with AD when compared with other groups (p<0.0001).A significant positive correlation was observed between ubiquitin, tau and apolipoprotein E ε4 genotype; with A β42 thecorrelation was negative. By comparing the effect size of the association between ubiquitin and a diagnosis of AD, wefind that high ubiquitin levels are specific for AD. We obtained an odds ratio of 5.6 (95% CI 5.0-7.7) for ubiquitin, towardsa diagnosis of AD based on clinical criteria, CSF biomarker signature (A β42+tau) and apolipoprotein Eε 4 genotype.Hence, all our findings taken together provide a strong statistical association linking ubiquitin to the pathology inAD. We also find that, the performance of ubiquitin as a diagnostic marker is comparable to that of CSF Aβ 42 or tau orapolipoprotein Eε 4 genotype considered individually.

Change in Body Mass Index Before and After Alzheimerµs Disease Onset by Yian Gu, Nikolaos Scarmeas, Stephanie Cosentino, Jason Brandt, Marilyn Albert, Deborah Blacker, Bruno Dubois, Yaakov Stern (349-356).
Objectives: A high body mass index (BMI) in middle-age or a decrease in BMI at late-age has been considered apredictor for the development of Alzheimer's disease (AD). However, little is known about the BMI change close to or afterAD onset. Methods: BMI of participants from three cohorts, the Washington Heights and Inwood Columbia Aging Project(WHICAP; population-based) and the Predictors Study (clinic-based), and National Alzheimer's Coordinating Center(NACC; clinic-based) were analyzed longitudinally. We used generalized estimating equations to test whether there weresignificant changes of BMI over time, adjusting for age, sex, education, race, and research center. Stratification analyses wererun to determine whether BMI changes depended on baseline BMI status. Results: BMI declined over time up to AD clinicalonset, with an annual decrease of 0.21 (p=0.02) in WHICAP and 0.18 (p=0.04) kg/m2 in NACC. After clinical onset of AD,there was no significant decrease of BMI. BMI even increased (b=0.11, p=0.004) among prevalent AD participants in NACC.During the prodromal period, BMI decreased over time in overweight (BMI≥ 25 and <30) WHICAP participants or obese(BMI ≥30) NACC participants. After AD onset, BMI tended to increase in underweight/normal weight (BMI<25) patientsand decrease in obese patients in all three cohorts, although the results were significant in NACC study only. Conclusions:Our study suggests that while BMI declines before the clinical AD onset, it levels off after clinical AD onset, and might evenincrease in prevalent AD. The pattern of BMI change may also depend on the initial BMI.

Understanding the Complexities of Functional Ability in Alzheimerµs Disease: More Than Just Basic and Instrumental Factors by Kristin Kahle-Wrobleski, Nicola Coley, Benoit Lepage, Christelle Cantet, Bruno Vellas, Sandrine Andrieu, PLASA/DSA Group (357-366).
Background: Dementia of the Alzheimer's type (AD) is defined by both cognitive and functional decline; newcriteria allow for identification of milder, non-functionally impaired patients. Understanding loss of autonomy in AD isessential, as later stages represent a significant burden and cost to patients, their families, and society. The purpose of thepresent analyses was to determine the factor structure of the Alzheimer's Disease Cooperative Study-Activities of DailyLiving Scale (ADCS-ADL) in a cohort of AD patients. Methods: Baseline ADCS-ADL assessments of 734 AD patientsfrom the PLASA study were included in an exploratory factor analysis (EFA). Because the ADCS-ADL was designed toassess change over time, change from baseline scores over 2 years were also analyzed using an EFA. Factorial solutionswere evaluated based on cross-loading, non-loadings, and number of items per factor. Results: Mean age at baseline was79.3, mean MMSE was 19.8 and 73.3% of participants were female. Baseline data suggested a 4-factor solution that includedfactors for basic ADLs (BADLs), domestic/household activities, communication/engagement with the environment,and outside activities. The change scores EFA suggested a 2-factor solution of BADLs and instrumental ADLs(IADLs). Conclusions: Distinct factors of IADLs should be considered for further validation as areas of attention to catchearly functional decline.

Advances in High-Field Magnetic Resonance Spectroscopy in Alzheimerµs Disease by Ningnannan Zhang, Xiaowei Song, Robert Bartha, Steven Beyea, Ryan D'Arcy, Yunting Zhang, Kenneth Rockwood (367-388).
Alzheimer's disease (AD) affects several important molecules in brain metabolism. The resulting neurochemicalchanges can be quantified non-invasively in localized brain regions using in vivo single-voxel proton magnetic resonancespectroscopy (SV 1H MRS). Although the often heralded diagnostic potential of MRS in AD largely remains unfulfilled,more recent use of high magnetic fields has led to significantly improved signal-to-noise ratios and spectral resolutions,thereby allowing clinical applications with increased measurement reliability. The present article provides a comprehensivereview of SV 1H MRS studies on AD at high magnetic fields (3.0 Tesla and above). This review suggests thatpatterned regional differences and longitudinal alterations in several neurometabolites are associated with clinically establishedAD. Changes in multiple metabolites are identifiable even at early stages of AD development. By combining informationof neurochemicals in different brain regions revealing either pathological or compensatory changes, high fieldMRS can be evaluated in AD diagnosis and in the detection of treatment effects. To achieve this, standardization of dataacquisition and analytical approaches is needed.

Altered Amplitude of Low-frequency Fluctuations in Early and Late Mild Cognitive Impairment and Alzheimer's Disease by Peipeng Liang, Jie Xiang, Hong Liang, Zhigang Qi, Kuncheng Li, Alzheimer's Disease NeuroImaging Initiative (389-398).
Purpose: Previous studies have shown that the strength of the low frequency fluctuation in the medial-linebrain areas are abnormally reduced in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. The purposeof this study was to explore the functional brain changes in early MCI (EMCI) and late MCI (LMCI) patients bymeasuring the amplitude of the blood oxygenation level dependent (BOLD) functional MRI (fMRI) signals at rest. Materialsand methods: 35 elderly normal controls (NC), 24 EMCI, 29 LMCI, and 14 AD patients from the Alzheimer's DiseaseNeuroimaging Initiative (ADNI2) were included in this study. Resting state fMRI and 3D structural MRI data wereacquired. The spatial patterns of spontaneous brain activity were measured by examining the amplitude of low-frequencyfluctuations (ALFF) of BOLD signal during rest. A one-way analysis of variance (ANOVA) was then performed on ALFFmaps, with age, sex and regional atrophy as covariates. Results: There were widespread ALFF differences among the fourgroups. As compared with controls, AD, LMCI and EMCI patients showed decreased ALFF mainly in the posterior cingulatecortex, precuneus, right lingual gyrus and thalamus (with a linear trend: NC>EMCI>LMCI>AD), while there was increasedactivity in the right parahippocampal gyrus (with a linear trend: NC<EMCI<LMCI<AD). Additionally, we alsoshowed that many regions with ALFF changes had significant correlations with the cognitive performance as measured bymini-mental state examination scores (MMSE) and the emotion states as measured by Geriatric Depression Scale (GDscale) for EMCI, LMCI and AD patients, but not for controls. Conclusion: Our results indicated that the significantly alteredALFF activities can be detected at EMCI stage, independent of age, sex and regional atrophy. The present study thussuggests ALFF abnormalities as a potential biomarker for the early diagnosis of AD and further provides insights into biologicalmechanisms of the diseases.

Does Semantic Memory Impairment in Amnestic MCI with Hippocampal Atrophy Conform to a Distinctive Pattern of Progression? by Davide Quaranta, Maria Gabriella Vita, Pietro Spinelli, Eugenia Scaricamazza, Diana Castelli, Giordano Lacidogna, Chiara Piccininni, Paolo Maria Rossini, Guido Gainotti, Camillo Marra (399-407).
Subjects with Mild Cognitive Impairment (MCI) are normally classified according to the presence of episodicmemory deficits associated or not to disturbances of other cognitive domains. The present study had two aims: to identifydiscrete subtypes of amnestic MCI (a-MCI) with hippocampal atrophy; and to assess if the identified subtypes show differentrates of progression to dementia. Sixty-seven a-MCI subjects were enrolled, all showing significant hippocampal atrophyon MRI. The subjects underwent at baseline and at follow-up a comprehensive neuropsychological examination,and were followed-up for five years to detect the conversion to dementia. An exploratory factor analysis on neuropsychologicalperformances at baseline identified three main factors that were subsequently used to perform a k-means clusteranalysis. Three cluster of a-MCI subjects were identified: “pure amnestic” (N=29), “multiple domain”(N=16), and“amnestic/semantic”(N=22). The successive discriminant functions were able to correctly classify 88% of the subjects.During the follow-up, 33 subjects converted to dementia (49.2%), 14 “pure amnestic” (48.3%), 11 “multiple domain”(68.5%) and 8 “amnestic/semantic” (36.4%; log-rank: p=0.016); median survival was respectively 36, 22, and 39 months.On Cox proportional hazard model, baseline MMSE (HR=0,709; p=0.006), education (HR=1,115; p=0.011) and belongingto the “multiple domain” subgroup (HR=2,706; p=0.013) were significantly associated to higher rate of conversion todementia. Our findings confirm the tendency to worst outcome of subjects with multiple domain MCI, and show that theassociation of episodic and semantic memory deficits, without other cognitive disturbances, could identify a specific cognitivepattern associated to slower cognitive decline, as previously reported in Alzheimer's Disease.

The Genetic Variation of ARRB2 is Associated with Late-onset Alzheimer's Disease in Han Chinese by Teng Jiang, Jin-Tai Yu, Ying-Li Wang, Hui-Fu Wang, Wei Zhang, Nan Hu, Lin Tan, Lei Sun, Meng-Shan Tan, Xi-Chen Zhu, Lan Tan (408-412).
Emerging evidence indicates that β-arrestin 2, an important regulator of G protein coupled receptors, is involvedin the pathogenesis of Alzheimer's disease (AD). The aim of this study was to investigate the association betweenβ -arrestin 2 gene (ARRB2) variation and the risk of late-onset AD (LOAD). A total of 1132 LOAD patients and 1158healthy controls from the Han Chinese population were included in this study. Initially, four common single nucleotidepolymorphisms (SNPs) (rs3786047, rs16954146, rs1045280 and rs2271167) were selected by consulting the Han Chinesefrom Beijing genotype data in HapMap database. Considering the fact that these four SNPs were located in one haplotypeblock and any two of them were in almost complete linkage disequilibrium (D'=1, r2≥0.897), we chose rs1045280 (a coding-synonymous variant) that covered all the common genetic variations in ARRB2 with r2≥0.8 as the tag SNP (tSNP) forthe subsequent genotyping. Our results showed that the minor allele of rs1045280 was associated with an increasedLOAD risk after adjusting for age, gender, educational level, and the apolipoprotein E (APOE) 4 status under dominant(OR=1.291; 95% CI: 1.063-1.568; Bonferroni-corrected P=0.03) and additive (OR=1.269; 95% CI: 1.069-1.507; Bonferroni-corrected P=0.018) models. Meanwhile, when these data were stratified by APOE ε4 status, this association was evidentonly in APOE ε4 carriers (OR=1.617; 95% CI: 1.01-2.588; P=0.045). In summary, this study provide the first evidencethat the tSNP of ARRB2 significantly increases LOAD risk in Han Chinese, suggesting ARRB2 may represent a susceptibilitygene for LOAD.