Journal of Alzheimer's Disease - Volume 22, issue 4

Authors: Chiasserini, Davide | Parnetti, Lucilla | Andreasson, Ulf | Zetterberg, Henrik | Giannandrea, David | Calabresi, Paolo | Blennow, Kaj

Article Type: Research Article

Abstract: Heart fatty acid binding protein (HFABP) has been proposed as a putative marker for dementia disorders. To evaluate the value of this protein as an early marker of Alzheimer's disease (AD), we analyzed HFABP level and the classical biomarkers amyloid-β (Aβ)1–42 , total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) followed up for four years (n = 41), AD (n = 32), and subjects with other neurological diseases without dementia (OND, n = 25). HFABP levels were higher in AD patients and in MCI converting to AD (MCI-AD) with respect …to OND and to cognitively stable MCI patients (MCI-MCI). The receiver operator characteristics analysis for HFABP alone showed a sensitivity of 87% and a specificity of 81% for AD versus OND (area under the curve, AUC = 0.83); sensitivity and specificity were 46% and 94%, respectively, when comparing MCI-MCI versus MCI-AD. CSF HFABP levels showed a strong positive correlation with both t-tau and p-tau. Interestingly, the ratio between HFABP and Aβ1–42 improved the performance in distinguishing AD from OND (sensitivity: 90%; specificity 82%, AUC = 0.89), and gave the best accuracy in discriminating MCI-AD from MCI-MCI (sensitivity: 80%; specificity 100%, AUC = 0.90). Survival analysis by means of Kaplan-Meier curve showed a significantly higher proportion of MCI patients converting to AD in the group with higher values of HFABP/Aβ1–42 ratio (cut-off = 0.7). A significant correlation between HFABP/Aβ1–42 ratio and MMSE annual decrease rate was also documented (p < 0.0001). HFABP/Aβ1–42 ratio might be a useful predictor of conversion in MCI patients. Show more

Keywords: Alzheimer's disease, amyloid-β1–42, biomarkers, cerebrospinal fluid, mild cognitive impairment, heart fatty acid binding protein, phosphorylated tau, total-tau

DOI: 10.3233/JAD-2010-101293

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1281-1288, 2010

Authors: Chen, Xuesong | Wagener, John F. | Morgan, Daniel H. | Hui, Liang | Ghribi, Othman | Geiger, Jonathan D.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized clinically by progressive disturbances in memory, judgment, reasoning, and olfaction, and pathologically by loss of synaptic integrity, extracellular accumulations of amyloid-β (Aβ) containing plaques, and intraneuronal tangles composed of hyperphosphorylated tau. Endolysosome dysfunction is one of the earliest pathological features of AD and cholesterol, a known risk factor for sporadic AD, is up-taken into neurons via receptor-mediated endocytosis. Accordingly, we determined the extent to which endolysosome dysfunction is associated with pathological features observed in rabbits fed cholesterol-enriched diet; a well-characterized model of sporadic AD. Olfactory bulbs were taken from rabbits fed for 12 weeks a …diet enriched with 2% cholesterol and endolysosome morphology and function as well as AD-like pathology were investigated using enzyme activity measurements, immunoblotting and immunostaining techniques. In olfactory bulbs of rabbits fed cholesterol-enriched diet, we observed enlarged endolysosomes containing increased accumulations of ApoB containing cholesterol and increased accumulations of synaptophysin, Aβ, and phosphorylated tau. The cholesterol-enriched diet also significantly decreased specific enzyme activities of the endolysosome enzymes acid phosphatase and cathepsin D. Decreased synaptic area was present in olfactory bulbs of cholesterol-fed rabbits as indicated by significant decreases in protein expression levels of the synaptic area marker protein synaptophysin. Our results suggest strongly that elevated circulating cholesterol plays an important role in the pathogenesis of AD, and that alterations in endolysosome structure and function are associated with cholesterol diet-induced AD-like pathology. Show more

Keywords: Acid phosphatase, amyloid-β protein, cathepsin D, cholesterol, endosomes, lysosomes, olfactory bulb, synaptophysin, tau proteins

DOI: 10.3233/JAD-2010-101323

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1289-1303, 2010

Authors: Diniz, Breno Satler | Teixeira, Antonio Lucio | Ojopi, Elida Benquique | Talib, Leda Leme | Mendonça, Vanessa Amaral | Gattaz, Wagner Farid | Forlenza, Orestes Vicente

Article Type: Research Article

Abstract: The activation of inflammatory cascades has been consistently demonstrated in the pathophysiology of Alzheimer's disease (AD). Among several putative neuroinflammatory mechanisms, the tumor necrosis factor α (TNF-α) signaling system has a central role in this process. Recent evidence indicates that the abnormal production of inflammatory factors may accompany the progression from mild cognitive impairment (MCI) to dementia. We aimed to examine serum levels of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in patients with MCI and AD as compared to cognitively unimpaired elderly subjects. We further aimed to investigate whether abnormal levels of these cytokines predict the progression from …MCI to AD upon follow-up. We utilized cross-sectional determination of serum levels of TNF-α, sTNFR1, and sTNFR2 (ELISA method) in a test group comprising 167 older adults (31 AD, 72 MCI, and 64 healthy controls), and longitudinal reassessment of clinical status after 18.9 ± 10.0 months. At baseline, there were no statistically significant differences in serum TNF-α, sTNFR1, and sTNFR2 between patients with MCI and AD as compared to controls. Nevertheless, patients with MCI who progressed to AD had significantly higher serum sTNFR1 levels as opposed to patients who retained the diagnosis of MCI upon follow-up (p = 0.03). Cox regression analysis showed that high serum sTNFR1 levels predicted the conversion from MCI to AD (p = 0.003), whereas no significant differences were found with respect to serum levels of TNF-α and sTNFR2. Abnormal activation of TNF-α signaling system, represented by increased expression of sTNFR1, is associated with a higher risk of progression from MCI to AD. Show more

Keywords: Alzheimer's disease, inflammation, mild cognitive impairment, pathophysiology, soluble tumor necrosis factor-α receptors, tumor necrosis factor-α

DOI: 10.3233/JAD-2010-100921

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1305-1311, 2010

Authors: Chen, Shufen | Townsend, Kirk | Goldberg, Terry E. | Davies, Peter | Conejero-Goldberg, Concepcion

Article Type: Research Article

Abstract: Tau aggregation in neurofibrillary tangles is a pathological hallmark in tauopathies including Alzheimer's disease (AD). The predominant aggregation of certain MAPT (tau gene) isoforms, either the 4-repeat (4R tau) or the 3-repeat (3R tau) isoform has been widely described in tauopathies. Alterations of the 4R tau to 3R tau ratio may be a key for tau-related neurodegeneration. To study the biological consequences in expression between tau splicing isoforms 4R and 3R, we analyzed the main neurobiological effects of inclusion of the repeat region coded by exon 10 in MAPT. We compared the transcriptional profiles of the 4R tau isoforms to …3R tau isoforms using whole-genome gene expression profiling microarrays using human neuroblastoma SH-SY5Y cell lines overexpressing either human 4R tau or 3R tau isoforms. We identified 68 transcripts that differed significantly (at p < 0.001) between 4R and 3R isoforms as conditioned on a second variant, the so-called 2N inclusion. We extended these findings in a 2 × 2 ANOVA to examine interaction effects of these variants. Transcripts involved in embryonic development were downregulated when exon 10 was present, while transcripts related to outgrowth of neurites were generally upregulated. An important pathway implicated in AD also differed between the 3R and 4R cell lines, Wnt signaling. These studies demonstrate expression differences between MAPT isoforms 4R tau and 3R tau due to the inclusion/exclusion of the repeat region coded for by exon 10. Our data add to complex findings on the role of 3R/4R in normal and abnormal neuronal function and highlight several molecular mechanisms that might drive neurodegeneration, or perhaps, set the stage for it. Show more

Keywords: Alzheimer's disease, gene expression profiling, microarrays, tau 3R, tau 4R

DOI: 10.3233/JAD-2010-101155

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1313-1329, 2010

Authors: Tierney, Mary C. | Moineddin, Rahim | Morra, Angela | Manson, Judith | Blake, Jennifer

Article Type: Research Article

Abstract: Long-term physical activity may affect risk of cognitive impairment but few studies have examined later life cognition in relation to intensity of life-long physical activity. We examined the associations between the intensity of long-term recreational physical activity and neuropsychological functioning in 90 healthy postmenopausal women on tests found to be useful in the early identification of dementia. Information was collected about their participation in strenuous and moderate activities between high school and menopause. Summary measures of long-term strenuous and moderate activity were constructed for each participant. All analyses were adjusted for relevant covariates. The six linear regression analyses showed significant …positive associations between moderate activity and Wechsler Adult Intelligence Scale Revised (WAIS-R), Digit Span backward, WAIS-R Digit Symbol, and Trail Making Test Part B. Significant negative relationships were found between strenuous activity and Rey Auditory Verbal Learning Test delayed verbal recall, Complex Figure Test delayed visual memory, WAIS-R Digit Span backward, category fluency, and WAIS-R Digit Symbol. The associations found in the present study suggest that while moderate activity may be protective, long-term strenuous activity before menopause may lower cognitive performance later in life. These results support further investigation of the effects of life-long exercise intensity on cognition in later life. Show more

Keywords: Cognition, exercise intensity, moderate activity, neuropsychological tests, strenuous activity

DOI: 10.3233/JAD-2010-101188

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1331-1338, 2010

Authors: Prestia, Annapaola | Drago, Valeria | Rasser, Paul E. | Bonetti, Matteo | Thompson, Paul M. | Frisoni, Giovanni B.

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) is defined by memory impairment with no impact on daily activities. 10 to 15% of MCI convert to Alzheimer's disease (AD) per year. While structural changes in the cortex of AD patients have been extensively investigated, fewer studies analyzed changes in the years preceding conversion. 46 MCI patients and 20 healthy controls underwent structural 1.0T-weighted high-resolution MR scans at baseline and after 1.4 (SD 0.3) years. All subjects were assessed yearly for up to 4 years with a comprehensive neuropsychological battery. Sixteen of the 46 patients converted to AD (cMCI) while 30 remained stable (sMCI). An …accurate voxel-based statistical mesh-model technique (cortical pattern matching) with a related region-of-interest analysis based on networks defined from a Brodmann area atlas (BAs) were used to map gray matter changes over time. At baseline, cMCI patients had 10 to 30% less cortical gray matter volume than healthy controls in regions known to be affected by AD pathology (entorhinal, temporoparietal, posterior cingulate, and orbitofrontal cortex, p = 0.0001). Over time, cMCI patients lost more gray matter than sMCI in all brain areas but mainly in the olfactory and in the polysynaptic hippocampal network (more than 8% gray matter loss, p < 0.024). sMCI patients had 10 to 20% less volume than controls in the posterior cingulate and orbitofrontal cortex (p < 0.008) although their progression over time was significantly slower than cMCI. AD patients in the MCI stage show greater gray matter loss in the olfactory and polysynaptic hippocampal network. These findings are in line with neuropathological knowledge. Show more

Keywords: Alzheimer's disease, cortical gray matter, early diagnosis, mild cognitive impairment, structural MRI

DOI: 10.3233/JAD-2010-101191

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1339-1349, 2010

Authors: Tokita, Yoriko | Kaji, Kentaro | Lu, Jun | Okura, Yoshio | Kohyama, Kuniko | Matsumoto, Yoh

Article Type: Research Article

Abstract: We recently demonstrated that newly developed non-viral amyloid-β (Aβ) DNA vaccines are safe and effective in reducing Aβ burdens in the brains of Alzheimer's disease (AD) model mice. The present study was undertaken to examine whether DNA vaccines effectively and safely reduce Aβ deposition in the brain of rhesus monkeys. For this purpose, DNA vaccines or empty vector at a dose of 3 mg were injected intramuscularly on a biweekly basis into rhesus monkeys (15–18 years old). Before and during vaccination, blood was drawn once a month and used for hematological and biochemical examinations. Six months after the first vaccination, …it was demonstrated that anti-Aβ antibodies in plasma of vaccinated monkeys were significantly elevated than that of control monkeys. Immunohistochemical examinations revealed that DNA vaccination reduced the Aβ burden to approximately 50% of that found in control monkeys (p = 0.026). There was neither inflammation nor microhemorrhage in the brain and no significant changes in cytokine and chemokine levels in the blood throughout the observation period. Taken together, DNA vaccination to monkeys is safe and effective in Aβ reduction and provides useful information for performing preclinical and clinical trials. Show more

Keywords: Alzheimer's disease, amyloid-β deposits, DNA vaccine, rhesus monkey

DOI: 10.3233/JAD-2010-100978

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1351-1361, 2010

Authors: Tayler, Hannah | Fraser, Thomas | Miners, J. Scott | Kehoe, Patrick G. | Love, Seth

Article Type: Research Article

Abstract: Oxidative damage is greater in brain tissue from patients with Alzheimer's disease (AD) than age-matched controls. The timing of this damage in relation to other pathogenic processes in AD remains unclear. We have examined the relationship of lipid peroxidation (thiobarbituric acid-reactive substances; TBARS) and antioxidant capacity (Trolox-equivalent) to APOE status, Braak tangle stage, amyloid-β (Aβ) plaque load, and the concentration of soluble and insoluble forms of Aβ, post-synaptic and dendritic spine proteins PSD95 and drebrin, β-secretase and Aβ-degrading enzymes neprilysin (NEP), insulin-degrading enzyme (IDE), and angiotensin-converting enzyme (ACE), in frontal, temporal, and parietal cortex from AD and control brains. Antioxidant …capacity was significantly elevated in AD and directly related to disease severity as indicated by Braak tangle stage and the amount of insoluble Aβ. APOE ε4 was associated with increased antioxidant capacity in AD but not controls. In contrast, apart from a reduction in TBARS in Braak stages III-IV in frontal cortex, this measure of oxidative damage did not change significantly with any indicator of disease severity. It was, however, higher in APOE ε4-positive than ε4-negative AD patients and correlated with β-secretase activity. Neither antioxidant capacity nor oxidative damage was related to the level of PSD95 or drebin or the activity of NEP, IDE, or ACE. Antioxidant capacity in AD is closely related to the level of insoluble Aβ and increases with pathological progression of the disease. Increased β-secretase activity associated with oxidative stress is likely to contribute to the accumulation of Aβ and this, in turn, to induce antioxidant capacity. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, angiotensin-converting enzyme, β-secretase, insulin-degrading enzyme, neprilysin, neurofibrillary tangles, oxidative stress, PSD95, synaptophysin

DOI: 10.3233/JAD-2010-101368

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1363-1373, 2010

Article Type: Other

DOI: 10.3233/JAD-2010-1432

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1375-1378, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-101369

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1379-1381, 2010