Current Alzheimer Research - Volume 11, Issue 4, 2014

Cortical atrophy and brain vascular disease are both associated with dementia, but there are only limited pathological data on the association of brain vascular disease with cortical atrophy. We studied pathological material from the Rush Memory and Aging Project (MAP, N = 445). Cortical and hippocampal atrophy, and atherosclerosis at the circle of Willis (large vessel disease, LVD) and arteriolosclerosis (small vessel disease, SVD) were rated by neuropathologists unaware of this study’s hypothesis. Quantitative measures of Alzheimer’s disease (AD) pathology, specifically neuronal neurofibrillary tangles (NFT) and amyloid–beta (Aβ) burden, were also obtained. Chronic micro and macroscopic infarcts were 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 the association of the most severe LVD (compared to the least) with cortical atrophy was 2.7 (CI: 1.5-4.7) p = 0.001; for hippocampal atrophy the odds ratio was 2.8 (CI: 1.5-5.2), p = 0.001. The association of SVD with atrophy did not follow a consistent 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 large autopsy study LVD was associated with cortical and hippocampal atrophy. The relationship between SVD and atrophy requires further study.

Intraneuronal amyloid-β (iAβ) accumulation has been demonstrated in Alzheimer disease (AD). Although extracellular amyloid 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 an analysis of hippocampal sections from a series of over 90 subjects with diverse antemortem clinical findings. In addition to AD cases, iAβ in pyramidal neurons was readily and reproducibly demonstrated in the majority of control cases. Similar findings for controls were made across all ages, spanning from infants to the elderly. There was no correlation of iAβ between gender, postmortem interval, or age. While the possible pathophysiological significance of iAβ accumulation in AD remains to be elucidated, careful examination of iAβ found in the normal brain may be informative for determining the biological role of iAβ and how this function changes during disease. Current findings support a physiological role for iAβ 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 by Aβ oligomers in the early stage of pathogenesis. We studied the levels of plasma Aβ monomers, Aβ oligomers, and soluble tumor necrosis factor α receptors (sTNFRs) in 120 controls, 32 amnestic mild cognitive impairment (aMCI) patients, and 90 mild AD patients. The plasma Aβ monomer, oligomer and sTNFR levels were measured by ELISA. We observed that the Aβ oligomer levels in mild AD patients were significantly higher than those in aMCI (200.8±83.8 versus 93.9±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 of aMCI and mild AD patients were significantly higher than the levels of control subjects. Moreover, the levels of both sTNFR1 and sTNFR2 were significantly correlated with A.β oligomer levels in aMCI (sTNFR1.r= 0.376, P= 0.034; sTNFR2r= 0.367, P= 0.039) and mild AD patients (sTNFR1.r= 0.471, P< 0.001; sTNFR2. r= 0.407, P< 0.001). More importantly, changes in Aβ oligomer and sTNFR levels accurately differentiated mild AD patients from control subjects, supporting these levels might be potential diagnostic biomarkers for aMCI and AD.

Glycosylation is one of the major post-translational modifications, required for proper folding and functions of glycoproteins. N-glycosylation in ER is mediated by oligosaccharyltransferase (OST), an enzyme complex transferring preassembled oligosaccharide to asparagine residues of nascent polypeptide chain. Our study here indicates that regulator of calcineurin 1 (RCAN1) can enhance N-glycosylation in ER, therefore elevates the activities of β- and γ-secretase and markedly increases Aβ 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 on transferrin whose glycosylation was only affected by OST catalytic subunit STT3A, suggesting the effect of RCAN1 is associated with RPN I in facilitating substrate delivery. Our previous studies have shown that RCAN1 was increased in AD brains and RCAN1 overexpression induced neuronal apoptosis. Here our study showed that RCAN1 further contributes to AD pathogenesis by increasing N-glycosylation and Aβ production.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Although, many putative biomarkers are reported for AD, only a few have been validated in the clinical setting. Ubiquitin levels increase in cerebrospinal fluid (CSF) of patients with AD, but its diagnostic value is not clear. In this present study we evaluate the performance of ubiquitin as a diagnostic marker and deduce a statistical association with disease pathology in AD. Ubiquitin levels were 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 Eε4 genotype; with Aβ42 the correlation was negative. By comparing the effect size of the association between ubiquitin and a diagnosis of AD, we find that high ubiquitin levels are specific for AD. We obtained an odds ratio of 5.6 (95% CI 5.0-7.7) for ubiquitin, towards a diagnosis of AD based on clinical criteria, CSF biomarker signature (Aβ42+tau) and apolipoprotein Eε4 genotype. Hence, all our findings taken together provide a strong statistical association linking ubiquitin to the pathology in AD. We also find that, the performance of ubiquitin as a diagnostic marker is comparable to that of CSF Aβ42 or tau or apolipoprotein Eε4 genotype considered individually.

Objectives: A high body mass index (BMI) in middle-age or a decrease in BMI at late-age has been considered a predictor for the development of Alzheimer’s disease (AD). However, little is known about the BMI change close to or after AD 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 were significant changes of BMI over time, adjusting for age, sex, education, race, and research center. Stratification analyses were run to determine whether BMI changes depended on baseline BMI status. Results: BMI declined over time up to AD clinical onset, 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) patients and 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 even increase in prevalent AD. The pattern of BMI change may also depend on the initial BMI.

Background: Dementia of the Alzheimer’s type (AD) is defined by both cognitive and functional decline; new criteria allow for identification of milder, non-functionally impaired patients. Understanding loss of autonomy in AD is essential, as later stages represent a significant burden and cost to patients, their families, and society. The purpose of the present analyses was to determine the factor structure of the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale (ADCS-ADL) in a cohort of AD patients. Methods: Baseline ADCS-ADL assessments of 734 AD patients from the PLASA study were included in an exploratory factor analysis (EFA). Because the ADCS-ADL was designed to assess change over time, change from baseline scores over 2 years were also analyzed using an EFA. Factorial solutions were evaluated based on cross-loading, non-loadings, and number of items per factor. Results: Mean age at baseline was 79.3, mean MMSE was 19.8 and 73.3% of participants were female. Baseline data suggested a 4-factor solution that included factors 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 catch early functional decline.

Alzheimer’s disease (AD) affects several important molecules in brain metabolism. The resulting neurochemical changes can be quantified non-invasively in localized brain regions using in vivo single-voxel proton magnetic resonance spectroscopy (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 comprehensive review of SV 1H MRS studies on AD at high magnetic fields (3.0 Tesla and above). This review suggests that patterned regional differences and longitudinal alterations in several neurometabolites are associated with clinically established AD. Changes in multiple metabolites are identifiable even at early stages of AD development. By combining information of neurochemicals in different brain regions revealing either pathological or compensatory changes, high field MRS can be evaluated in AD diagnosis and in the detection of treatment effects. To achieve this, standardization of data acquisition and analytical approaches is needed.

Purpose: Previous studies have shown that the strength of the low frequency fluctuation in the medial-line brain areas are abnormally reduced in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) patients. The purpose of this study was to explore the functional brain changes in early MCI (EMCI) and late MCI (LMCI) patients by measuring the amplitude of the blood oxygenation level dependent (BOLD) functional MRI (fMRI) signals at rest. Materials and methods: 35 elderly normal controls (NC), 24 EMCI, 29 LMCI, and 14 AD patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI2) were included in this study. Resting state fMRI and 3D structural MRI data were acquired. The spatial patterns of spontaneous brain activity were measured by examining the amplitude of low-frequency fluctuations (ALFF) of BOLD signal during rest. A one-way analysis of variance (ANOVA) was then performed on ALFF maps, with age, sex and regional atrophy as covariates. Results: There were widespread ALFF differences among the four groups. As compared with controls, AD, LMCI and EMCI patients showed decreased ALFF mainly in the posterior cingulate cortex, precuneus, right lingual gyrus and thalamus (with a linear trend: NC>EMCI>LMCI>AD), while there was increased activity in the right parahippocampal gyrus (with a linear trend: NC

Subjects with Mild Cognitive Impairment (MCI) are normally classified according to the presence of episodic memory deficits associated or not to disturbances of other cognitive domains. The present study had two aims: to identify discrete subtypes of amnestic MCI (a-MCI) with hippocampal atrophy; and to assess if the identified subtypes show different rates of progression to dementia. Sixty-seven a-MCI subjects were enrolled, all showing significant hippocampal atrophy on 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 neuropsychological performances at baseline identified three main factors that were subsequently used to perform a k-means cluster analysis. 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 belonging to the “multiple domain” subgroup (HR=2,706; p=0.013) were significantly associated to higher rate of conversion to dementia. Our findings confirm the tendency to worst outcome of subjects with multiple domain MCI, and show that the association of episodic and semantic memory deficits, without other cognitive disturbances, could identify a specific cognitive pattern associated to slower cognitive decline, as previously reported in Alzheimer’s Disease.

Emerging evidence indicates that β-arrestin 2, an important regulator of G protein coupled receptors, is involved in the pathogenesis of Alzheimer’s disease (AD). The aim of this study was to investigate the association between β-arrestin 2 gene (ARRB2) variation and the risk of late-onset AD (LOAD). A total of 1132 LOAD patients and 1158 healthy controls from the Han Chinese population were included in this study. Initially, four common single nucleotide polymorphisms (SNPs) (rs3786047, rs16954146, rs1045280 and rs2271167) were selected by consulting the Han Chinese from Beijing genotype data in HapMap database. Considering the fact that these four SNPs were located in one haplotype block 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) for the subsequent genotyping. Our results showed that the minor allele of rs1045280 was associated with an increased LOAD 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 evident only in APOE ε4 carriers (OR=1.617; 95% CI: 1.01-2.588; P=0.045). In summary, this study provide the first evidence that the tSNP of ARRB2 significantly increases LOAD risk in Han Chinese, suggesting ARRB2 may represent a susceptibility gene for LOAD.