Journal of Alzheimer's Disease - Volume 21, issue 4

Authors: Jellinger, Kurt A. | Attems, Johannes

Article Type: Research Article

Abstract: The prevalence of both Alzheimer's disease (AD) and vascular dementia (VaD) increase with advancing age, but epidemiologic data above age 85 are imprecise and inconsistent. A retrospective hospital-based study of the prevalence and pathology of VaD was performed in 1700 consecutive autopsy cases of demented elderly in Vienna, Austria (mean age 84.3 ± 5.4 SD; 90% over age 70). It assessed clinical and general autopsy data and neuropathology including immunohistochemistry. Neuropathologic diagnosis followed current consensus criteria. Four age groups (7th to 10th decade) were evaluated. “Pure” VaD (due to cerebrovascular disease without other pathologies; neuritic Braak stages 1.2–1.6) was observed …in 12.3% of the total cohort, decreasing between age 60 and 90+ from 15.0 to 8.7%. Morphologic subtypes (subcortical arteriosclerotic encephalopathy, multi-infarct encephalopathy, and strategic infarct dementia) showed no age-related differences. By contrast, AD (without concomitant pathologies; 45.6% of total), mixed dementia (AD + cerebrovascular encephalopathy; 5.5%), and AD with minor cerebrovascular lesions (22.3%) increased with age. The relative prevalence of AD + Lewy pathology (9.3%) remained fairly stable, whereas other dementias (5.0%) decreased significantly over age 90. 85% of the patients with "pure" VaD had histories of diabetes, 75% of stroke(s), 95% morphologic signs of hypertension, 65% myocardial infarction (recent and old ones), 97% cerebral hypertonic-arteriosclerotic microangiopathy (associated with cerebral amyloid angiopathy in 23%) and 90% severe atherosclerosis of large cerebral arteries. Similar autopsy findings were seen in mixed dementia (MIX) and in AD + minor cerebrovascular lesions. Major vascular lesions differed between VaD and MIX, VaD showing more than 60% subcortical infarcts, MIX only 43% such lesions. This retrograde hospital-based study using strict morphologic diagnostic criteria confirmed the existence of “pure” VaD in old age, with a tendency to decline after age 90, while AD and AD + cerebrovascular pathologies showed considerable age-related increase, and "pure" AD slightly decreasing after age 90. Show more

Keywords: Autopsy study, cerebral amyloid angiopathy, mixed dementia, multi-infarct dementia, subcortical arteriosclerotic encephalopathy, vascular dementia

DOI: 10.3233/JAD-2010-100603

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1283-1293, 2010

Authors: Sehlin, Dag | Söllvander, Sofia | Paulie, Staffan | Brundin, RoseMarie | Ingelsson, Martin | Lannfelt, Lars | Pettersson, Frida Ekholm | Englund, Hillevi

Article Type: Research Article

Abstract: Amyloid-β (Aβ) oligomers of different sizes and forms have recently been the focus for many Alzheimer's disease (AD) researchers. Various immunoassays have been used to detect low concentrations of these elusive Aβ species in different forms of human samples using little or no sample dilutions. However, the possibility that positive results may be caused by interference from heterophilic antibodies (HA) is often overlooked. HA, which recognize immunoglobulins from other species, are present in human plasma and cerebrospinal fluid (CSF) and may cause interference in sandwich immunoassays like enzyme-linked immunosorbent assays (ELISAs) by cross-binding the capture and detection antibodies of the …assay. They thus may generate a false positive signal. Here we show that when assessing the Aβ oligomer content in plasma samples from 44 individuals with a sandwich ELISA, none of the 21 positive signals remained when the assay was repeated in the presence of factors blocking HA. Similarly, in CSF samples from 104 individuals, the signals from the 22 positive samples were strongly reduced when analyzed after anti-HA treatment. Taken together, HA interference is a problem that needs to be addressed when measuring low levels of an antigen in human plasma and CSF samples. Show more

Keywords: Amyloid-β, cerebrospinal fluid, ELISA, false positive signals, heterophilic antibodies, oligomers, plasma

DOI: 10.3233/JAD-2010-100609

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1295-1301, 2010

Authors: Mandal, Pravat K. | Bhavesh, Neel Sarovar | Chauhan, Virender S. | Fodale, Vincenzo

Article Type: Research Article

Abstract: Oligomerization of amyloid-β peptide (Aβ) is an important stage in Alzheimer's disease. Recently, it has been shown that in an experimental model, smaller sized (e.g., isoflurane, desflurane, etc.) anesthetics induce Aβ oligomerization. Using state-of-the-art solution nuclear magnetic resonance, spectroscopic studies on Aβ interaction with propofol indicated that propofol does not interact with the G29, A30, and I31 residues of Aβ peptide at a clinically relevant concentration (0.0832 mM), and no Aβ oligomerization was observed after 69 days. However, Aβ oligomerization was observed when treated with propofol (clinically relevant concentration) coadministered with aqueous halothane solution. Furthermore, dose dependence studies at various …propofol concentrations (0.32 mM, 2.07 mM, and 53.4 mM) indicate the effect of propofol concentration on Aβ oligomerization revealing the hydrophobic nature of interactions between propofol with these critical residues. These experimental findings reaffirm that smaller molecular sized anesthetics (e.g., halothane) do play a leading role in Aβ oligomerization. Show more

Keywords: Aβ oligomerization, amyloid-β peptide, clinically relevant concentration, halothane, NMR, propofol

DOI: 10.3233/JAD-2010-100396

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1303-1309, 2010

Authors: Li, Yan | Chu, Leung-Wing | Wang, Binbin | Yik, Ping-Yiu | Huriletemuer, | Jin, Dong-Yan | Ma, Xu | Song, You-Qiang

Article Type: Research Article

Abstract: We here demonstrate that promoter polymorphisms rs8003602 and rs3783320 of cholesterol 24S-hydroxylase (CYP46A1) were significantly associated with Alzheimer's disease (AD) in Chinese subjects. Haplotype analyses showed that haplotype CG is the risk haplotype. Either single marker or haplotypic association was found only in the APOE ε4 negative group. The association was then replicated in an independent set of case-control samples in Mongolians. We also investigated the function of promoter haplotypes and found that luciferase expression for TA promoter construct exhibited significantly higher expression level than the risk CG promoter construct. This finding might indicate individuals bearing the CG haplotype are …genetically more susceptible to AD compared to those with TA haplotype. Further, we found MYT1 could be the potential transcription factor binding to the significant promoter polymorphism and mediated gene transcriptional activity. In general, our results show that promoter haplotypes could significantly affect CYP46A1 gene transcription level possibly through interacting with certain transcription factors. Show more

Keywords: Allelic expression, Alzheimer's disease, case-control study, CYP46A1

DOI: 10.3233/JAD-2010-100765

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1311-1323, 2010

Authors: Atti, Anna Rita | Forlani, Claudia | De Ronchi, Diana | Palmer, Katie | Casadio, Paola | Dalmonte, Edoardo | Fratiglioni, Laura

Article Type: Research Article

Abstract: A total of 7,389 dementia-free elderly (60–102 years old) enrolled in the "Faenza Project" (Northern Italy) were clinically evaluated by nurses and physicians with the aim of detecting the independent and combined association of medical and social factors with cognitive status. Cognitive Impairment No Dementia (CIND) was defined for MMSE scores ⩽ 2 standard deviations than the age- and education-corrected mean score obtained by the non-demented persons of the Faenza cohort. Logistic Regression analysis was used to estimate Odds Ratios and 95% Confidence Intervals (OR, 95%CI) for CIND. The diagnostic procedure identified 402 (5.4%) CIND cases. Diabetes (OR, 95%CI=1.6, 1.2–2.2), …stroke (OR, 95%CI=1.9, 1.4–2.6), and depressive symptoms (OR, 95%CI=1.9, 1.4–2.7) emerged as the most relevant medical comorbidities of CIND. Low education (OR, 95%CI=1.8, 1.1–2.9), low Socio Economic Status (SES) (OR, 95%CI=1.5, 1.1–2.1), and unmarried status (OR, 95%CI=1.7, 1.2–2.5) were associated with CIND. Medical and social factors were independently related to CIND occurrence. In comparison to subjects without any of the above mentioned conditions, subjects with one medical and one social factor had an OR, 95%CI for CIND equal to 6.0, 2.9–12.4. The strength of the association increased when more of those conditions occurred in combination, suggesting a synergistic effect. Despite some methodological limitations, data from this cross-sectional population-based Italian study show that low education, low SES, unmarried status together with diabetes, stroke, and depressive symptoms are related to cognitive impairment in the general population. The interaction of medical and social factors further increases the probability of CIND. Show more

Keywords: Cognitive impairment, cognitive impairment no dementia (CIND), comorbidity, depression, diabetes, epidemiology, stroke

DOI: 10.3233/JAD-2010-091618

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1325-1334, 2010

Authors: Chu, Leung-Wing | Tam, Sidney | Wong, Rachel L.C. | Yik, Ping-Yiu | Song, Youqiang | Cheung, Bernard M.Y. | Morley, John E. | Lam, Karen S.L.

Article Type: Research Article

Abstract: There is a paucity of data on the relationship between testosterone and Alzheimer's disease (AD) in older men. The objective of the present study was to investigate the effects of serum total testosterone (TT), bioavailable testosterone (BT), and sex hormone binding globulin (SHBG) levels on the subsequent risk of AD in non-demented Chinese older men. This was a one-year prospective cohort study. 153 ambulatory community-living non-demented Chinese older men, aged 55 years or over, were recruited and followed for one year. Morning serum TT, BT, and SHBG levels were measured at baseline. At one-year of follow-up, assessment for dementia and …AD were performed. AD was diagnosed by the NINCDS-ADRDA criteria for probable AD. Overall, the mean age of the subjects was 72.7 (SD 6.9). 6.5% (n = 10) developed dementia (converters), all having AD. 93.5% (n = 143) did not develop dementia (non-converters). Logistic regression analysis for independent predictors of AD~showed that the baseline serum BT level, systolic blood pressure (SBP) and ApoE ε4 genotype were significant independent predictors, after adjustment for age, education, BMI, fasting plasma glucose, and serum HDL-C levels. The baseline serum BT level predicted a reduced risk of AD (adjusted relative risk (RR) 0.22, 95% CI: 0.07–0.69)). Baseline SBP and ApoE ε4 genotype but not SHBG were independent risk factors, with RRs of 1.04 and 5.04 respectively. In conclusion, the serum level of bioavailable testosterone in late life predicts a lower risk of future AD development in older men. Show more

Keywords: Aging, Alzheimer's disease, Chinese, men, testosterone

DOI: 10.3233/JAD-2010-100027

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1335-1345 , 2010

Authors: Pengas, George | Patterson, Karalyn | Arnold, Robert J. | Bird, Chris M. | Burgess, Neil | Nestor, Peter J.

Article Type: Research Article

Abstract: The neural network activated during Topographical Memory (TM) tasks in controls overlaps with the earliest affected regions in Alzheimer's disease (AD) but not with those of Semantic Dementia (SD). This suggests that clinical TM tests could be more bespoke to neural dysfunction in early AD and therefore more sensitive and specific. We hypothesized that TM impairment would be characteristic of AD but not of SD making it useful both for early diagnosis and differential diagnosis. TM was assessed in 69 patients (22 mild AD, 15 SD, 32 with mild cognitive impairment (MCI)) and 35 controls, using three tasks: the four …mountains test and two novel tests in a virtual town (the Virtual Route Learning Test (VRLT) and the Heading Orientation Test). AD patients were impaired on all TM tasks. The VRLT was the most discriminatory; had the highest correlation with caregiver reports of navigation problems; and correlated strongly with memory, attention/executive function, and to a lesser degree, visuospatial ability. In contrast, SD patients performed well on the TM battery only becoming abnormal with very advanced dementia and performance correlated exclusively with attention/executive function. The VRLT achieved 95% sensitivity and 94% specificity in discriminating AD patients from controls; at the same cut-off, 70% of MCI patients were impaired. When combined with either naming performance or global dementia severity, there was complete separation of AD from SD. The VRLT is ecologically valid, highly sensitive to early AD, and useful in discriminating AD from the non-Alzheimer dementia, SD. Show more

Keywords: Mild cognitive impairment, topographical memory, virtual environment

DOI: 10.3233/JAD-2010-100654

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1347-1365, 2010

Authors: Balducci, Claudia | Tonini, Raffaella | Zianni, Elisa | Nazzaro, Cristiano | Fiordaliso, Fabio | Salio, Monica | Vismara, Lorenzo | Gardoni, Fabrizio | Di Luca, Monica | Carli, Mirjana | Forloni, Gianluigi

Article Type: Research Article

Abstract: Synaptic dysfunction is an early event in the development of Alzheimer's disease (AD) and relates closely to the cognitive impairment characterizing this neurodegenerative process. A causative association has been proposed, largely on the basis of in vitro studies, between memory decline, soluble amyloid-β (Aβ) oligomers and alterations of glutamatergic neurotransmission. We aimed here to characterize in vivo N-methyl-D-aspartate receptor (NMDAR)-mediated signaling, at an early stage of AD, before extracellular amyloid plaques are deposited. We assessed the functional link between cognitive abilities and NMDAR-mediated pharmacological responses of six-month-old AβPP23 transgenic mice (AβPP23tg), overexpressing the human amyloid-β protein precursor carrying the Swedish …double mutation. We found evidence of cognitive impairments in these mice, indicated by deficits in the delayed-non-matching-to-place task. Alterations of NMDAR-mediated signaling in this mouse model were confirmed by the reduced sensitivity of motor-activation and working memory to pharmacological inhibition of NMDAR activity. At the molecular level, AβPP23tg mice show hippocampal alterations in the trafficking of synaptic NMDAR subunits NR2A and NR2B and at an ultrastructural analysis show Aβ oligomers intracellularly localized in the synaptic compartments. Importantly, the behavioral and biochemical alterations of NMDAR signaling are associated with the inhibition of long-term synaptic potentiation and inversion of metaplasticity at CA1 synapses in hippocampal slices from AβPP23tg mice. These results indicate a general impairment of synaptic function and learning and memory in young AβPP23tg mice with Aβ oligomers but no amyloid plaques. Show more

Keywords: Alzheimer's disease, amyloid-β oligomers, AβPP23 Tg mice, NMDA glutamate receptors, spatial memory, synaptic plasticity

DOI: 10.3233/JAD-2010-100675

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1367-1381, 2010

Authors: Iuliano, Luigi | Monticolo, Roberto | Straface, Giuseppe | Spoletini, Ilaria | Gianni, Walter | Caltagirone, Carlo | Bossù, Paola | Spalletta, Gianfranco

Article Type: Research Article

Abstract: Oxidative stress, which contributes to neuronal damage, is thought to be a pathophysiological mechanism of Alzheimer's disease (AD). Markers of oxidative stress may appear early in the preclinical, mild cognitive impairment (MCI) phase of AD. We investigated the interaction among enzymatic-derived oxysterols (24S-hydroxycholesterol and 27-hydroxycholesterol), markers of oxidative stress, including free radical-related oxysterols (7β-hydroxycholesterol and 7-ketocholesterol), and vitamin E in AD patients and two amnestic MCI subtypes, amnestic single-domain MCI (a-MCI) subjects, and multi-domain MCI (md-MCI) subjects, compared to healthy control subjects (HC). The study included 37 patients with AD, 24 with a-MCI, 29 with md-MCI, and 24 HC. Plasma …assessments were made using isotope dilution-mass spectrometry. Although we found no significant change in free radical- or enzymatic-derived oxysterol concentrations in AD or MCI patients, vitamin E levels corrected for cholesterol were reduced in AD patients compared to HC. Results suggest that AD patients have upregulated cerebral oxidative stress or a nutritional deficit of vitamin E. The oxysterols investigated here are not useful markers for diagnosing AD or MCI. Show more

Keywords: Alzheimer's disease, amnestic, cholesterol, mild cognitive impairment, oxysterols, vitamin E

DOI: 10.3233/JAD-2010-100780

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1383-1392, 2010

Authors: Brennan-Krohn, Thea | Salloway, Stephen | Correia, Stephen | Dong, Matthew | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: CADASIL is a genetic vascular dementia caused by mutations in the Notch 3 gene on Chromosome 19. However, little is known about the mechanisms of vascular degeneration. We characterized upstream components of Notch signaling pathways that may be disrupted in CADASIL, by measuring expression of insulin, IGF-1, and IGF-2 receptors, Notch 1, Notch 3, and aspartyl-(asparaginyl)-β-hydroxylase (AAH) in cortex and white matter from 3 CADASIL and 6 control brains. We assessed CADASIL-associated cell loss by measuring mRNA corresponding to neurons, oligodendroglia, and astrocytes, and indices of vascular degeneration by measuring smooth muscle actin (SMA) and endothelin-1 expression in isolated vessels. …Immunohistochemical staining was used to assess SMA degeneration. Significant abnormalities, including reduced cerebral white matter mRNA levels of Notch 1, Notch 3, AAH, SMA, IGF receptors, myelin-associated glycoproteins, and glial fibrillary acidic protein, and reduced vascular expression of SMA, IGF receptors, Notch 1, and Notch 3 were detected in CADASIL-lesioned brains. In addition, we found CADASIL-associated reductions in SMA, and increases in ubiquitin immunoreactivity in the media of white matter and meningeal vessels. No abnormalities in gene expression or immunoreactivity were observed in CADASIL cerebral cortex. In conclusion, molecular abnormalities in CADASIL are largely restricted to white matter and white matter vessels, corresponding to the distribution of neuropathological lesions. These preliminary findings suggest that CADASIL is mediated by both glial and vascular degeneration with reduced expression of IGF receptors and AAH, which regulate Notch expression and function. Show more

Keywords: Aspartyl-(asparaginyl)-β-hydroxylase, human, Notch, vascular dementia, white matter degeneration

DOI: 10.3233/JAD-2010-100036

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1393-1402, 2010

Article Type: Editorial

DOI: 10.3233/JAD-2010-101543

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1403-1408, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-100035

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1409-1410, 2010