Journal of Alzheimer's Disease - Volume 8, issue 1

Authors: Boutté, Angela M. | Neely, M. Diana | Bird, Thomas D. | Montine, Kathleen S. | Montine, Thomas J.

Article Type: Research Article

Abstract: Neuronal microtubules are morphologically abnormal in diseased regions of brain from patients with late-onset Alzheimer's disease (LOAD). Here we tested the hypothesis that tubulin derived from gray matter of patients with multiple forms of dementia was functionally impaired. Following taxol/GTP stimulation of tubulin polymerization of gray matter extracts we observed reduced capacity of tubulin to polymerize in LOAD, but not individuals with mild cognitive impairment (MCI), compared to controls. Moreover, we observed similarly reduced taxol/GTP-stimulated tubulin polymerization from gray matter obtained from patients with AD caused by PSEN2 N141I mutation or frontotemporal dementia with parkinsonism linked to chromosome-17 caused (FTDP-17) …by TAU V337M or P301L mutation. Our results show that modification of tubulin function may contribute to intermediate or late stages in the pathogenesis of sporadic and inherited AD as well as FTDP-17. Show more

Keywords: Alzheimer's disease, presenilin 2, frontotemporal dementia with parkinsonism linked to chromosome-17, mild cognitive impairment, tubulin, microtubules

DOI: 10.3233/JAD-2005-8101

Citation: Journal of Alzheimer's Disease, vol. 8, no. 1, pp. 1-6, 2005

Authors: Yu, Xiaoyi | Caltagarone, John | Smith, Mark A | Bowser, Robert

Article Type: Research Article

Abstract: DNA damage and activation of the cell cycle have been implicated in numerous neurodegenerative diseases, including Alzheimer disease, Parkinson's disease, and amyotrophic lateral sclerosis. To better understand the role of cell cycle proteins in DNA-damage induced neuronal cell death, we examined various cell cycle proteins during camptothecin-induced death of human neuroblastoma cells. We report a rapid induction of p53 and increased expression of p21, concurrent with reduced levels of many cell cycle proteins that regulate G1 to S phase cell cycle progression. However, we found increased levels of cdk2 and cyclin E, and formation of a cyclin E-cdk2-p21 protein complex. …DNA damage failed to induce activation and progression of the cell cycle. Finally, camptothecin-induced neuronal cell death occurred concurrent with phosphorylation of histone H2B. Pretreatment of cells with cdk inhibitor olomoucine impeded cdk2-cyclin E accumulation, but not the induction of p53. Olomucine concurrently delayed histone H2B phosphorylation, caspase-3 activation and cell death. These findings suggest that DNA-damage of differentiated neuroblastoma cells induces a rapid p53-mediated inhibition of cell cycle progression and induction of cdk2-cyclin E, followed by caspase-3 activation, phosphorylation of histone and cell death. Show more

Keywords: Cyclin-dependent kinase, neuroblastoma, DNA damage, cell cycle, histone H2B, p53

DOI: 10.3233/JAD-2005-8102

Citation: Journal of Alzheimer's Disease, vol. 8, no. 1, pp. 7-21, 2005

Authors: Pajonk, Frank-Gerald | Kessler, Holger | Supprian, Tillmann | Hamzei, Pegah | Bach, Daniela | Schweickhardt, Janina | Herrmann, Wolfgang | Obeid, Rima | Simons, Andreas | Falkai, Peter | Multhaup, Gerd | Bayer, Thomas A.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a devastating brain disorder clinically characterised by progressive loss of characteristic cognitive abilities. Increasing evidence suggests a disturbed copper (Cu) homeostasis to be associated with the pathological processes. In the present study we analysed the plasma Cu levels and cognitive abilities using the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-cog) in 32 patients with mild to moderate AD. Statistical analysis revealed a negative correlation between plasma Cu levels and cognitive decline (r=−0.49; P<0.01). Patients with low plasma Cu (mean 82 ± SD 9) had significant higher ADAS-cog values (mean 23 ± SD 7), than patients with medium …plasma Cu (mean 110 ± SD 7), who exhibited lower ADAS-cog scores (mean 16 ± SD 4; ANOVA, P<0.0001). Despite the fact that all patients had plasma Cu levels within the physiological range between 65μg and 165μg/dL, 87.5% of the patients revealed a significant negative correlation between plasma Cu and ADAS-cog. This finding supports the hypothesis of a mild Cu deficiency in most AD patients. Show more

Keywords: Copper, ceruloplasmin, ADAS-cog, cognition, serum

DOI: 10.3233/JAD-2005-8103

Citation: Journal of Alzheimer's Disease, vol. 8, no. 1, pp. 23-27, 2005

Authors: Luna-Muñoz, José | García-Sierra, Francisco | Falcón, Viviana | Menéndez, Ivón | Chávez-Macías, Laura | Mena, Raúl

Article Type: Research Article

Abstract: Neurofibrillary tangles (NFTs) are the neuropathological hallmarks in Alzheimer's disease (AD). Densities of NFTs correlate with the dementia status. NFTs reflect the intracellular accumulation of abnormal paired helical filaments (PHFs) composed of the microtubule-associated protein tau. Hyperphosphorylation and truncation have been proposed as key events leading to the genesis of PHFs. A recent hypothesis involving conformational changes has been emerging. These structural modifications of the tau protein were detected by monoclonal antibodies (mAbs) recognizing discontinous epitopes along the tau molecule such as Alz-50, Tau-66 and MC1. A new mAb, TG-3, detects an early pathology in AD. The epitope of mAb …TG-3 maps to phosphorylated Thr231 when the tau molecule is conformationally altered. In the present study, we used confocal microscopy to analyze the state of tau molecule adopting the TG-3 conformation during tangle formation. We also compared mAb TG-3 immunoreactivity with that of mAb Alz-50. Immunoelectronmicroscopy was also performed. N- and C- termini markers evidenced that the tau molecule is intact when it adopts the TG-3 conformation. In addition to NFT, mAb TG-3 also recognized NFT-not bearing-neurons suggesting an early processing of tau prior to NFT formation. Ultrastructural analysis evidenced the presence of TG-3 and Alz-50 immunoreactive products on organelles including mitochondria and endoplasmic reticulum. Nuclear heterochromatin was densely immunolabelled. These results together with the fact that TG-3 immunoreactivity is related to intact tau suggest that the conformation recognized by TG-3 is early staged in the neuronal pathology of AD. In addition, we document that the earliest changes in tau occur closely associated with organelles and heterochromatin. Show more

Keywords: Alzheimer's disease, Tau protein, conformational changes, mAb TG-3, mAb Alz-50, neurofibrillary tangle, paired helical filaments, confocal microscopy

DOI: 10.3233/JAD-2005-8104

Citation: Journal of Alzheimer's Disease, vol. 8, no. 1, pp. 29-41, 2005

Authors: Hill, Jerrold | Fillit, Howard | Shah, Sonali N. | del Valle, Megan C. | Futterman, Robert

Article Type: Research Article

Abstract: Background: While vascular dementia (VaD) is the second most prevalent dementia diagnosis, little is known about healthcare use and costs for VaD. Purpose: This study compares the healthcare use and costs of community-dwelling patients with VaD to patients with Alzheimer's disease (AD), other dementias (OD), cerebrovascular disease without dementia (CVD), and patients without dementia or cerebrovascular disease (controls). Methods: Using diagnoses codes from medical claims and encounter records, 678 VaD, 1,722 AD, 957 OD, 2,718 CVD, and 14,023 controls were identified from patients enrolled in a 100,000-member group practice Medicare HMO during 1999–2002. Annual healthcare use …and costs of the study groups were compared, using regression analysis to control for patient characteristics. Results: VaD patients had the highest annual costs, $14,387, followed by $10,716 for OD, $8,254 for CVD, and $7,839 for AD, and $5,494 for controls (p<0.0001 for all comparisons to VaD). Despite higher total direct costss, VaD patients had lower costs for physician visits and prescription drugs compared with all study groups except OD. In contrast, CVD patients had the highest costs for these services. Moreover, hospital admissions for VaD were nearly twice those for CVD, and hospital days for VaD nearly three times those for CVD, despite the high prevalence of cardiovascular conditions for both VaD and CVD. Conclusions: VaD patients had higher healthcare costs compared to all other patient groups. The substantially higher costs for VaD compared to CVD and the differences in use of healthcare services by VaD compared to CVD suggest that dementia, not cerebrovascular disease, is a major source of the cost differences. Lower costs for physician visits and prescription drugs for VaD suggest possible opportunities for improving ambulatory care and preventing high-cost hospitalizations. Show more

Keywords: Vascular dementia, healthcare cost, healthcare utilization, Alzheimer's disease

DOI: 10.3233/JAD-2005-8105

Citation: Journal of Alzheimer's Disease, vol. 8, no. 1, pp. 43-50, 2005

Authors: Kaye, J.A. | Moore, M.M. | Dame, A. | Quinn, J. | Camicioli, R. | Howieson, D. | Corbridge, E. | Care, B. | Nesbit, G. | Sexton, G.

Article Type: Research Article

Abstract: To determine if rates and locations of brain volume loss associated with AD are phase-specific, occurring prior to clinical onset and at later stages, we performed longitudinal volumetric MRI analysis on 155 subjects enrolled in a prospective study of aging and dementia. Subjects were divided by Clinical Dementia Rating (CDR) scale into stages of Normal (CDR 0 → 0), Very Mild (CDR 0 → 0.5 and 0.5 → 0.5), Mild (CDR 0.5 → 1.0 and 1.0 → 1.0) and Moderate (CDR 1.0 → 2.0 and 2.0 → 2.0) dementia. Rates of volume change in CSF spaces, lobar and medial temporal …lobe regions were analyzed for group differences across stages. Annual rates of ventricular volume change differed between non-demented and very mild group (p<0.01). In later severity stages, ventricular, temporal, basal ganglia-thalamic region and total volumes show change. Rates of volume loss increase as dementia progresses, but not uniformly in all regions. These regional and phase-specific volume changes form targets for monitoring disease-modifying therapies at clinically relevant, defined stages of dementia. Show more

Keywords: Aging, oldest-old, MRI, dementia, Alzheimer disease

DOI: 10.3233/JAD-2005-8106

Citation: Journal of Alzheimer's Disease, vol. 8, no. 1, pp. 51-56, 2005

Authors: Attems, Johannes | König, Claudia | Huber, Monika | Lintner, Felix | Jellinger, Kurt A.

Article Type: Research Article

Abstract: Few studies evaluated cause of death (COD) in elderly demented and non-demented people, the majority based on death certificates alone. The present study is based on autopsy reports with neuropathological examination of 308 inpatients (58.1% female) over age 60 years (mean: 83.5, SD: +/−8.6). CODs were classified into seven groups. The most common were bronchopneumonia (n=117; 38%) and cardiovascular disease (n=116, 37.7%). In 176 patients (57.1%) neuropathology was indicative for dementia: 76.7% Alzheimer disease (AD), 4.5% vascular dementia, 4.0% mixed type dementia (AD + vascular dementia), and 14.8% other dementias. Main COD significantly differed in demented and non-demented patients: bronchopneumonia …(45.5% in demented versus 28.0% in non-demented), cardiovascular disease (46.2% in non-demented versus 31.3% in demented). Whereas there were significant differences in COD between AD patients and non-demented ones (bronchopneumonia versus cardiovascular disease), no differences were seen between the latter and patients with other types of dementia than AD. Our data emphasize the high incidence of bronchopneumonia as a COD in patients suffering from AD Show more

Keywords: Cause of death, dementia, Alzheimer disease, autopsy, bronchopneumonia, cardiovascular disease

DOI: 10.3233/JAD-2005-8107

Citation: Journal of Alzheimer's Disease, vol. 8, no. 1, pp. 57-62, 2005

Authors: Cook, Casey N. | Hejna, Matthew J. | Magnuson, Debra J. | Lee, John M.

Article Type: Research Article

Abstract: Protein phosphatase 2B (calcineurin) activity has been shown to be decreased in Alzheimer's disease and is a possible mechanism(s) for the hyperphosphorylation of tau and subsequent neurofibrillary tangle formation. Recently, mRNA expression of Down's syndrome Critical Region 1 gene, which encodes the protein calcipressin (an endogenous inhibitor of calcineurin), was found to be upregulated in both Down's syndrome and Alzheimer's disease. Calcipressin is induced by oxidative stress and Aβ in vitro, further establishing a link in the pathology of both diseases. Using immunohistochemistry techniques, calcipressin protein expression in the pyramidal neurons of the temporal lobe was shown to increase with …aging (r2 =0.5658; p=0.0313), and also in moderate to severe Alzheimer's disease compared to control patients (t=3.872; p=0.0017). In addition, there was a positive correlation between the total number of calcipressin-positive pyramidal neurons and the number of neurofibrillary tangles in the temporal cortex (r2 = 0.5955; p=0.0249). As there was an 88% increase in nuclear calcipressin in Alzheimer's disease (p=0.0001), the relationship between cellular localization of calcipressin and neurofibrillary tangle formation was investigated, which revealed a decrease in neurofibrillary tangle-bearing neurons that contain nuclear calcipressin (t=4.874; p=0.0028) and further demonstrates that the cellular regulation of calcipressin is altered in Alzheimer's disease. Show more

Keywords: Calcipressin, calcineurin, Alzheimer's disease, aging, tau, amyloid β, oxidative stress

DOI: 10.3233/JAD-2005-8108

Citation: Journal of Alzheimer's Disease, vol. 8, no. 1, pp. 63-73, 2005

Article Type: Discussion

DOI: 10.3233/JAD-2005-8109

Citation: Journal of Alzheimer's Disease, vol. 8, no. 1, pp. 75-80, 2005

Article Type: Book Review

DOI: 10.3233/JAD-2005-8110

Citation: Journal of Alzheimer's Disease, vol. 8, no. 1, pp. 81-81, 2005