Journal of Alzheimer's Disease - Volume 17, issue 2

Authors: O'Bryant, Sid E. | Hobson, Valerie | Hall, James R. | Waring, Stephen C. | Chan, Wenyan | Massman, Paul | Lacritz, Laura | Cullum, C. Munro | Diaz-Arrastia, Ramon

Article Type: Research Article

Abstract: The current search for biomarkers that are diagnostic and/or prognostic of Alzheimer's disease (AD) is of vital importance given the rapidly aging population. It was recently reported that brain-derived neurotrophic factor (BDNF) fluctuated according to AD severity, suggesting that BDNF might have utility for diagnostics and monitoring of therapeutic efficacy. The current study sought to examine whether BDNF levels varied according to AD severity, as previously reported. There were 196 participants (Probable AD, n = 98; Controls, n = 98) in the Texas Alzheimer's Research Consortium (TARC) Longitudinal Research Cohort available for analysis. BDNF levels were assayed via multiplex immunoassay. …Regression analyses were utilized to examine the relation between BDNF levels, Mini-Mental Status Examination, and Clinical Dementia Rating scores adjusting for age and gender. In adjusted models, BDNF levels did not distinguish between AD patients and normal controls and did not significantly predict AD severity or global cognitive functioning. In conclusion, these findings do not support the notion that BDNF serves as a diagnostic marker for AD or disease severity. It is likely that the most accurate approach to identifying biomarkers of AD will be through an algorithmic approach that combines multiple markers reflective of various pathways. Show more

Keywords: Alzheimer's disease, biomarkers, brain-derived neurotrophic factor, clinical dementia rating, dementia severity

DOI: 10.3233/JAD-2009-1051

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 337-341, 2009

Authors: Sedaghat, Fereshteh | Dedousi, Eleni | Costa, Vasiliki | Dimitriadis, Athanasios S. | Baloyannis, Stavros J.

Article Type: Research Article

Abstract: The aggregation of amyloid-β42 (Aβ42 ) constitutes one of the major pathogenic events in Alzheimer's disease (AD), and the study of regional cerebral blood flow (rCBF), using single photon emission computed tomography (SPECT), aids the diagnosis of AD. In this study, we evaluated whether there was a correlation between rCBF in brain regions and plasma levels of Aβ1-42 in AD. 29 patients (mean age 71 ± 9) with a diagnosis of AD who fulfilled NINCDS-ADRDA criteria with a mean Mini-Mental Status Examination score of 15 ± 9 and 16 normal controls (mean age 64 ± 8) underwent SPECT …brain imaging with hexamethylpropylene amine oxime, and semiquantitative analysis of rCBF was performed. Plasma samples were collected the same day of the SPECT and plasma Aβ1-42 measured by ELISA. A significant reduction of rCBF was observed in most regions in AD compared to controls, whereas mean plasma Aβ42 did not differ between the two groups. There was no correlation between rCBF in any region and plasma Aβ42 nor any correlations between gender, age, and severity with plasma levels of Aβ42 . Since rCBF is coupled to neuronal activity, we conclude that plasma Aβ1-42 concentration is independent of neuronal function in every single region of the brain. Show more

Keywords: Alzheimer's disease, brain SPECT, cerebral blood flow, plasma amyloid β42

DOI: 10.3233/JAD-2009-1056

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 343-348, 2009

Authors: Moretti, Davide Vito | Pievani, Michela | Fracassi, Claudia | Binetti, Giuliano | Rosini, Sandra | Geroldi, Cristina | Zanetti, Orazio | Rossini, Paolo M. | Frisoni, Giovanni B.

Article Type: Research Article

Abstract: We evaluated the association between amygdalo-hippocampal complex (AHC) atrophy and two electroencephalography (EEG) markers of cognitive decline: increase of theta/gamma and increase of alpha3/alpha2 relative power ratio. Seventy-nine subjects with mild cognitive impairment (MCI) underwent EEG recording and magnetic resonance imaging scan. Based on the tertiles values of decreasing AHC volume, three groups of AHC growing atrophy were obtained. The groups were characterized by the performance to cognitive tests and theta/gamma and alpha3/alpha2 relative power ratio. AHC atrophy is associated with memory deficits as well as with increase of theta/gamma and alpha3/alpha2 ratio. Moreover, when the amygdalar and hippocampal volume …are separately considered within AHC, the increase of theta/gamma ratio is best associated with amygdalar atrophy whereas alpha3/alpha2 ratio is best associated with hippocampal atrophy. AHC atrophy is associated with memory deficits and EEG markers of cognitive decline. So far, these EEG markers could have a prospective value in differential diagnosis between patients with MCI who develop dementia and those who do not as well as between MCI patients who will develop Alzheimer's disease and those who develop non-Alzheimer's disease dementias. The alterations of the functional connections, inducing global network pathological changes, in the whole AHC could better explain MCI state. Show more

Keywords: Amygdalo-hippocampal complex, cognitive tests, electroencephalography, gamma rhythm, mild cognitive impairment, theta rhythm

DOI: 10.3233/JAD-2009-1059

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 349-357, 2009

Authors: Golanska, Ewa | Hulas-Bigoszewska, Krystyna | Sieruta, Monika | Zawlik, Izabela | Witusik, Monika | Gresner, Sylwia M. | Sobow, Tomasz | Styczynska, Maria | Peplonska, Beata | Barcikowska, Maria | Liberski, Pawel P. | Corder, Elizabeth H.

Article Type: Research Article

Abstract: We studied eight polymorphisms within APOE, PRNP, PRND, and CYP46 genes in 213 Polish late-onset patients with Alzheimer's disease (AD) and 171 non-demented elderly controls. A latent classification approach, grade-of-membership analysis, was taken to identify three extreme pure type risk sets defined by the probabilities of being affected with AD and for genotypes found at the examined genes. Sets I and II represented high intrinsic risk, having a higher density of various genotypes compared to set III, at low intrinsic risk. A gradient of onset age depending on membership in the risk sets was also observed. Logistic regression analysis showed …that the highest risk for AD was found for individuals who co-inherited APOE ε4 allele, PRNP codon 129 homozygosity, PRND codon 174 Thr allele, and CYP46 rs754203 g allele. AD can be influenced by genetic profiles leading to appearance of the disease, composed of genes which separately evoke a little or unnoticeable effect. Moreover, there may be multiple sufficient risk sets for AD. Looking at multiple genes together rather than analyzing them individually, may improve identification of risk alleles. Show more

Keywords: Alzheimer's disease, APOE, CYP46, genetic polymorphisms, grade-of-membership analysis, multiple genetic risk factors, PRND, PRNP

DOI: 10.3233/JAD-2009-1055

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 359-368, 2009

Authors: Basselin, Mireille | Nguyen, Henry N. | Chang, Lisa | Bell, Jane M. | Rapoport, Stanley I.

Article Type: Research Article

Abstract: Donepezil, an acetylcholinesterase (AChE) inhibitor used for treating Alzheimer's disease patients, is thought to act by increasing brain extracellular acetylcholine (ACh), and ACh binding to cholinergic receptors. Muscarinic receptors are coupled to cytosolic phospholipase A2 (cPLA2 ) activation and arachidonic acid (AA) release from synaptic membrane phospholipid. This activation can be imaged in rodents as an AA incorporation coefficient k*, using quantitative autoradiography. Acute and chronic effects of donepezil on the AA signal, k* for AA, were measured in 81 brain regions of unanesthetized rats. Twenty min after a single oral dose (3.0 mg/kg) of donepezil, k* was increased …significantly in 37 brain regions, whereas k* did not differ from control 7 h afterwards or following chronic (21 days) of donepezil. Pretreatment with atropine prevented the 20-min increments in k* following donepezil. Donepezil also increased the brain ACh concentration and reduced brain AChE activity, but did not change cPLA2 activity, regardless of administration regimen. These results show that donepezil acutely increases the brain AA signal that is mediated by ACh acting at muscarinic receptors, but that this signal is rapidly desensitized despite continued elevated brain ACh concentration. In contrast, the AA signal in response to arecoline was not altered following donepezil. Show more

Keywords: Acetylcholine, acetylcholinesterase, Alzheimer's disease, anticholinesterase, arachidonic acid, brain, desensitization, donepezil, imaging, muscarinic receptors, phospholipase A2

DOI: 10.3233/JAD-2009-1058

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 369-382, 2009

Authors: Bernardi, Livia | Geracitano, Silvana | Colao, Rosanna | Puccio, Gianfranco | Gallo, Maura | Anfossi, Maria | Frangipane, Francesca | Curcio, Sabrina A.M. | Mirabelli, Maria | Tomaino, Carmine | Vasso, Franca | Smirne, Nicoletta | Maletta, Raffaele | Bruni, Amalia C.

Article Type: Research Article

Abstract: Mutations in the amyloid-β protein precursor (AβPP) gene can cause autosomal dominant early-onset Alzheimer's disease, or Alzheimer's disease (AD) associated with cerebral amyloid angiopathy (CAA), cerebral hemorrhage, or both. We have previously reported that the AβPP A713T mutation is associated with AD and subcortical ischemic lesions at magnetic resonance imaging in a large family which neuropathology confirmed CAA, stroke, and AD lesions. The objective of this clinical and molecular study was to investigate AβPP gene mutations in 59 patients affected by AD with cerebrovascular lesions (CVLs) and a family history of dementia. We identified three affected subjects with the AβPP …A713T mutation. Since the prevalence of this mutation worldwide is very low, a common founder could exist in southern Italy. The pathogenicity of this mutation was confirmed and the clinical AD phenotype with CVLs seems to be a distinctive feature in the southern Italian population. The identification of these patients suggests that genetic epidemiology in large cohorts of familial late onset AD with CVLs would increase the probability of identifying AβPP mutations. Show more

Keywords: Alzheimer's disease, amyloid-β, AβPP A713T mutation, cerebrovascular lesions, vascular risk factors, white matter lesions

DOI: 10.3233/JAD-2009-1061

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 383-389, 2009

Authors: Burns, David H. | Rosendahl, Scott | Bandilla, Dirk | Maes, Olivier C. | Chertkow, Howard M. | Schipper, Hyman M.

Article Type: Research Article

Abstract: There are currently no accepted blood-based biomarkers of sporadic Alzheimer's disease (AD). Augmented oxidative stress has been implicated in both neural and peripheral AD tissues. In this study, we determined whether short-wavelength near-infrared (NIR) spectrophotometry of blood plasma differentiates mild sporadic AD from normal aging. NIR analysis was conducted on 75 μl plasma samples from 19 AD, 27 amnestic MCI, and 17 normal elderly control (NEC) persons using an optical fiber-coupled, holographic grating-based NIR spectrograph. Five spectral bands associated with heme, R-CH, R-OH, H2 O, and R-NH functional groups were sensitive to oxidative modification in pre-clinical studies and were pre-selected …to develop a logistic regression model for sample classification. This model differentiated AD from NEC samples with a sensitivity of 80% and specificity of 77%. Fifteen and twelve MCI patients were classified with the NEC and AD groups, respectively. The spectra were not influenced by age, gender, exposure to cholinesterase inhibitors or vitamin E, or sample storage time. The NIR data further implicate oxidative stress in the systemic pathophysiology of sporadic AD and differentiate mild (and possibly pre-clinical) AD from NEC individuals with moderate-high accuracy. The procedure is minimally-invasive, rapid, relatively-inexpensive, and may provide a useful biological marker of sporadic AD. Show more

Keywords: Alzheimer disease, biomarker, diagnosis, mild cognitive impairment, near-infrared, oxidative stress, spectroscopy

DOI: 10.3233/JAD-2009-1053

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 391-397, 2009

Authors: Zilkens, Renate R. | Spilsbury, Katrina | Bruce, David G. | Semmens, James B.

Article Type: Research Article

Abstract: Dementia-related healthcare planning requires accurate information on dementia patient characteristics and hospitalization trends at a population level. This population-based retrospective cohort study was designed to evaluate factors associated with total hospital length-of-stay (tLOS) in the last year of life (1990–2005) in Western Australians with dementia. Using linked hospital and death records, 29,884 dementia cases were identified. The average tLOS in the last year of life for all cases was 31.8 days. tLOS was longer for vascular dementia than Alzheimer's disease (41 versus 28 days; Rate Ratio (RR) 1.4; 95% CI 1.3–1.6). After multivariate adjustment, tLOS was longer for males than …females (RR 1.4; 95% CI 1.3–1.4); longer for remote (RR 1.7; 95% CI 1.4–2.0) and very remote (RR 3.0; 95% CI 2.4–3.9) compared to metropolitan areas; and shorter with increasing age. 62% of admissions were emergency admissions. "Problems accessing alternative medical facilities" and "problems related to care provider dependency" accounted for a total of 16.4% of all bed days. In conclusion, people with dementia spend a considerable period of time in the hospital during their last year of life. Consideration of geographic isolation and accessibility to non-hospital facilities in dementia-related healthcare planning may liberate in-patient beds for more elective and acute care admissions. Show more

Keywords: Alzheimer's disease, data-linkage, dementia, hospital use, last year of life

DOI: 10.3233/JAD-2009-1057

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 399-407, 2009

Authors: Jing, Zheng | Caltagarone, John | Bowser, Robert

Article Type: Research Article

Abstract: c-Abl is a non-receptor tyrosine kinase that participates in multiple signaling pathways linking the cell surface, cytoskeleton, and the nucleus. Recent in vitro studies have also linked c-Abl to amyloid-β-induced toxicity and tau phosphorylation. To further characterize a potential role of c-Abl in Alzheimer's disease (AD), we examined the expression and distribution of total and phosphorylated forms of c-Abl in the hippocampus of AD and control subjects. Laser scanning confocal microscopy was used to examine the colocalization of c-Abl with AD pathology. Our results demonstrate alterations in the presence and distribution of c-Abl and phosphorylated isoforms of c-Abl within the …hippocampus during AD. Total unphosphorylated c-Abl was highest in non-demented control hippocampus. Activated isoforms of c-Abl were most abundant in AD hippocampus and co-localized with AD pathology, including granulovacuolar degeneration bodies. c-Abl interacts with phosphorylated tau in AD brain and may contribute to the formation of tau pathology. These studies demonstrate altered activation and distribution of c-Abl during AD, suggesting a role for c-Abl in Aβ signal transduction and generation of tau pathology in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, c-Abl, granulovacuolar degeneration bodies, tau

DOI: 10.3233/JAD-2009-1062

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 409-422, 2009

Authors: Grossi, Cristina | Francese, Simona | Casini, Angela | Rosi, Maria Cristina | Luccarini, Ilaria | Fiorentini, Anna | Gabbiani, Chiara | Messori, Luigi | Moneti, Gloriano | Casamenti, Fiorella

Article Type: Research Article

Abstract: Clioquinol (CQ) is a "metal protein attenuating compound" that crosses the blood-brain barrier and binds, with high affinity, copper(II) and zinc(II), two metal ions critically involved in amyloid-β aggregation and toxicity. CQ was recently proposed for the treatment of Alzheimer's disease, but controversial data have been reported so far concerning its real therapeutic advantages. We describe here results of chronic CQ treatment in the TgCRND8 mouse model of Alzheimer's disease. Remarkably, based on classical behavioral tests, CQ treatment was found to revert, to a large extent, the working memory impairments that are characteristic of this mouse model. Pairwise, a significant …reduction of amyloid-β plaque burden, both in the cortex and in the hippocampus, was detected as well as an attenuation of astrogliosis. MALDI Mass Spectrometry Imaging technique revealed a specific localization of CQ in the above mentioned brain areas. Modest but significant effects on the absolute and relative brain concentrations of the three most important biometals (i.e., copper, zinc, and iron) were highlighted following CQ treatment. The pharmacological and mechanistic implications of the above findings are thoroughly discussed. Show more

Keywords: Alzheimer's disease, amyloid-β burden, behavioral tests, clioquinol, ICP-OES, MALDI-MSI, TgCRND8 mice

DOI: 10.3233/JAD-2009-1063

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 423-440, 2009

Authors: Sato, Noriko | Ueki, Akinori | Ueno, Hideo | Shinjo, Hidetaka | Morita, Yoshio

Article Type: Research Article

Abstract: Dopamine D3 receptor (DRD3) is present in the limbic system, which is thought to regulate affect, cognition, and activity. Thus a functional change in the DRD3 gene could in turn affect the cognitive and psychiatric symptoms of dementia of Alzheimer's type (DAT). We investigated a possible association of DRD3 genotype with DAT and the behavioral and psychological symptoms of dementia (BPSD) in mild DAT. The genotyping for DRD3 and apolipoprotein E (ApoE) was determined using restriction fragment length polymorphism in 210 patients with mild DAT and 224 age- and sex-matched non-demented controls. The occurrence of BPSD during the course of …mild dementia was demonstrated using the Behavioral Pathology in Alzheimer's Disease rating scale (BEHAVE-AD). No significant differences in DRD3 genotype were identified between DAT and controls, regardless of ApoE ε4. Among the DAT with BPSD, however, a significant association was observed between the presence of the DRD3 glycine allele and paranoid and delusional ideation, regardless of ApoE ε4. In conclusion, DRD3 gene polymorphism is unlikely to play a substantial role in conferring susceptibility to DAT, but it may be involved in the development of paranoid and delusional ideation during the course of mild DAT. Show more

Keywords: Behavioral and psychological symptoms of dementia (BPSD), delusional ideation, dementia of Alzheimer's type, dopamine D3 receptor, gene polymorphism, paranoid ideation, Ser9Gly

DOI: 10.3233/JAD-2009-1054

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 441-448, 2009

Article Type: Discussion

DOI: 10.3233/JAD-2009-1085

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 449-452, 2009

Article Type: Announcement

DOI: 10.3233/JAD-2009-1102

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 453-455, 2009