Journal of Alzheimer's Disease - Volume 17, issue 3

Authors: Peterson, Dylan W. | George, Roshni C. | Scaramozzino, Francesca | LaPointe, Nichole E. | Anderson, Richard A. | Graves, Donald J. | Lew, John

Article Type: Research Article

Abstract: An aqueous extract of Ceylon cinnamon (C. zeylanicum) is found to inhibit tau aggregation and filament formation, hallmarks of Alzheimer's disease (AD). The extract can also promote complete disassembly of recombinant tau filaments and cause substantial alteration of the morphology of paired-helical filaments isolated from AD brain. Cinnamon extract (CE) was not deleterious to the normal cellular function of tau, namely the assembly of free tubulin into microtubules. An A-linked proanthocyanidin trimer molecule was purified from the extract and shown to contain a significant proportion of the inhibitory activity. Treatment with polyvinylpyrolidone effectively depleted all proanthocyanidins from the extract solution …and removed the majority, but not all, of the inhibitory activity. The remainder inhibitory activity could be attributed to cinnamaldehyde. This work shows that compounds endogenous to cinnamon may be beneficial to AD themselves or may guide the discovery of other potential therapeutics if their mechanisms of action can be discerned. Show more

Keywords: Aggregation, Alzheimer's disease, cinnamaldehyde, cinnamon extract, filaments, proanthocyanidin, tau

DOI: 10.3233/JAD-2009-1083

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 585-597, 2009

Authors: Kirsch, Wolff | McAuley, Grant | Holshouser, Barbara | Petersen, Floyd | Ayaz, Muhammad | Vinters, Harry V. | Dickson, Cindy | Haacke, E. Mark | Britt III, William | Larsen, James | Kim, Ivan | Mueller, Claudius | Schrag, Matthew | Kido, Daniel

Article Type: Research Article

Abstract: A new iron sensitive MR sequence (susceptibility weighted imaging – SWI) enabling the simultaneous quantitation of regional brain iron levels and brain microbleeds (BMB) has been acquired serially to study dementia. Cohorts of mildly cognitively impaired (MCI) elderly (n = 73) and cognitively normal participants (n = 33) have been serially evaluated for up to 50 months. SWI phase values (putative iron levels) in 14 brain regions were measured and the number of BMB were counted for each SWI study. SWI phase values showed a left putaminal mean increase of iron (decrease of phase values) over the study duration in …27 participants who progressed to dementia compared to Normals (p = 0.035) and stable MCI (p = 0.01). BMB were detected in 9 out of 26 (38%) MCI participants who progressed to dementia and are a significant risk factor for cognitive failure in MCI participants [risk ratio = 2.06 (95% confidence interval 1.37–3.12)]. SWI is useful to measure regional iron changes and presence of BMB, both of which may be important MR-based biomarkers for neurodegenerative diseases. Show more

Keywords: Amyloid angiopathy, brain, cognitive impairment, dementia, globus pallidal iron, microbleeds, putaminal iron, susceptibility weighted imaging

DOI: 10.3233/JAD-2009-1073

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 599-609, 2009

Authors: Nelson, Valery M. | Dancik, Chanteé M. | Pan, Weiying | Jiang, Zhi-Gang | Lebowitz, Michael S. | Ghanbari, Hossein A.

Article Type: Research Article

Abstract: Oxidative stress plays a significant role in neurotoxicity associated with a variety of neurodegenerative diseases including Alzheimer's disease (AD). Increased oxidative stress has been shown to be a prominent and early feature of vulnerable neurons in AD. Olfactory neuroepithelial cells are affected at an early stage. Exposure to oxidative stress induces the accumulation of intracellular reactive oxygen species (ROS), which in turn causes cell damage in the form of protein, lipid, and DNA oxidations. Elevated ROS levels are also associated with increased deposition of amyloid-β and formation of senile plaques, a hallmark of the AD brain. If enhanced ROS exceeds …the basal level of cellular protective mechanisms, oxidative damage and cell death will result. Therefore, substances that can reduce oxidative stress are sought as potential drug candidates for treatment or preventative therapy of neurodegenerative diseases such as AD. PAN-811, also known as 3-aminopyridine-2-carboxaldehyde thiosemicarbazone or Triapine, is a small lipophilic compound that is currently being investigated in several Phase II clinical trials for cancer therapy due to its inhibition of ribonucleotide reductase activity. Here we show PAN-811 to be effective in preventing or reducing ROS accumulation and the resulting oxidative damages in both AD-derived and age-matched olfactory neuroepithelial cells. Show more

Keywords: Alzheimer's disease, neuroprotection, olfactory neuroepithelium (ON), oxidative stress, PAN-811

DOI: 10.3233/JAD-2009-1078

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 611-619, 2009

Authors: Claassen, Jurgen A.H.R. | Diaz-Arrastia, Ramon | Martin-Cook, Kristin | Levine, Benjamin D. | Zhang, Rong

Article Type: Research Article

Abstract: Cerebrovascular disease may contribute to the development and progression of Alzheimer's disease (AD). This study investigated whether impairments in cerebral hemodynamics can be detected in early-stage AD. Nine patients with mild AD and eight cognitively normal controls matched for age underwent brain magnetic resonance imaging and neuropsychological evaluation, followed by assessment of steady-state cerebral blood flow velocity (CBFV, transcranial Doppler), blood pressure (BP, Finapres), and cerebrovascular resistance index (BP/CBFV). Cerebral hemodynamics were quantified using spectral and transfer function analysis of BP and CBFV in rest, during standing up after squat, and during repeated squat-stand maneuvers. Compared to controls, AD patients …had lower CBFV and higher cerebrovascular resistance index, unexplained by brain atrophy. Low-frequency variability of BP was enhanced, suggesting impaired arterial baroreflex function. However, CBFV variability was reduced despite enhanced BP variability, and dynamic cerebral autoregulation was not impaired. In conclusion, despite a distinct pattern of altered cerebral hemodynamics, AD patients may have normal autoregulation. However, the challenges for autoregulation in AD are higher, as our data show enhanced BP fluctuations. Increased cerebral vasoconstriction or reduced vasomotion also may attenuate CBFV variability. Show more

Keywords: Alzheimer's disease, cardiovascular physiology, cerebral autoregulation, transcranial Doppler ultrasonography

DOI: 10.3233/JAD-2009-1079

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 621-629, 2009

Authors: Tian, Qing | Zhang, Jun-Xia | Zhang, Yao | Wu, Feng | Tang, Qian | Wang, Cheng | Shi, Zhi-Yong | Zhang, Jing-Hui | Liu, Sang | Wang, Yue | Zhang, Qi | Wang, Jian-Zhi

Article Type: Research Article

Abstract: To explore the role of protein kinase A (PKA) in regulating tau phosphorylation and spatial memory, we injected forskolin, an activator of PKA, at different concentrations into the rat brains. We found that forskolin at concentrations up to 80 μM enhanced tau phosphorylation and was associated with prominent spatial memory impairment. Higher concentrations of forskolin, up to 200 μM, were associated with reduced phosphorylation levels of tau and no memory deficits. Forskolin elevated cAMP and activated PKA in a dose-dependent manner. When infused at 200 μM, forskolin also resulted in the activation and overexpression of protein phosphatase-2A (PP-2A) and attenuated …the okadaic acid-induced PP-2A inhibition. These data suggest that the upregulation of PKA by forskolin to a certain level may activate PP-2A but that the latter can ameliorate the PKA-induced tau phosphorylation and memory impairment in the rats. Show more

Keywords: Alzheimer's disease, forskolin, phosphorylation, protein kinase A, protein phosphatase-2A, tau

DOI: 10.3233/JAD-2009-1088

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 631-642, 2009

Authors: Ferrarini, Luca | Frisoni, Giovanni B. | Pievani, Michela | Reiber, Johan H.C. | Ganzola, Rossana | Milles, Julien

Article Type: Research Article

Abstract: In this study, we investigated the use of hippocampal shape-based markers for automatic detection of Alzheimer's disease (AD) and mild cognitive impairment converters (MCI-c). Three-dimensional T1-weighted magnetic resonance images of 50 AD subjects, 50 age-matched controls, 15 MCI-c, and 15 MCI-non-converters (MCI-nc) were taken. Manual delineations of both hippocampi were obtained from normalized images. Fully automatic shape modeling was used to generate comparable meshes for both structures. Repeated permutation tests, run over a randomly sub-sampled training set (25 controls and 25 ADs), highlighted shape-based markers, mostly located in the CA1 sector, which consistently discriminated ADs and controls. Support vector machines …(SVMs) were trained, using markers from either one or both hippocampi, to automatically classify control and AD subjects. Leave-1-out cross-validations over the remaining 25 ADs and 25 controls resulted in an optimal accuracy of 90% (sensitivity 92%), for markers in the left hippocampus. The same morphological markers were used to train SVMs for MCI-c versus MCI-nc classification: markers in the right hippocampus reached an accuracy (and sensitivity) of 80%. Due to the pattern recognition framework, our results statistically represent the expected performances of clinical set-ups, and compare favorably to analyses based on hippocampal volumes. Show more

Keywords: Alzheimer's disease, hippocampus, magnetic resonance images, mild cognitive impairment, morphological markers, support vector machines

DOI: 10.3233/JAD-2009-1082

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 643-659, 2009

Authors: Arendash, Gary W. | Mori, Takashi | Cao, Chuanhai | Mamcarz, Malgorzata | Runfeldt, Melissa | Dickson, Alexander | Rezai-Zadeh, Kavon | Tan, Jun | Citron, Bruce A. | Lin, Xiaoyang | Echeverria, Valentina | Potter, Huntington

Article Type: Research Article

Abstract: We have recently shown that Alzheimer's disease (AD) transgenic mice given a moderate level of caffeine intake (the human equivalent of 5 cups of coffee per day) are protected from development of otherwise certain cognitive impairment and have decreased hippocampal amyloid-β (Aβ) levels due to suppression of both β-secretase (BACE1) and presenilin 1 (PS1)/γ-secretase expression. To determine if caffeine intake can have beneficial effects in "aged" APPsw mice already demonstrating cognitive impairment, we administered caffeine in the drinking water of 18–19 month old APPsw mice that were impaired in working memory. At 4–5 weeks into caffeine treatment, those impaired transgenic …mice given caffeine (Tg/Caff) exhibited vastly superior working memory compared to the continuing impairment of control transgenic mice. In addition, Tg/Caff mice had substantially reduced Aβ deposition in hippocampus (↓ 40% and entorhinal cortex (↓46%), as well as correlated decreases in brain soluble Aβ levels. Mechanistically, evidence is provided that caffeine suppression of BACE1 involves the cRaf-1/NFκB pathway. We also determined that caffeine concentrations within human physiological range effectively reduce active and total glycogen synthase kinase 3 levels in SweAPP N2a cells. Even with pre-existing and substantial Aβ burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD. Show more

Keywords: Alzheimer's disease, Alzheimer's transgenic mice, amyloid-β, caffeine, cognitive impairment, memory, treatment

DOI: 10.3233/JAD-2009-1087

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 661-680, 2009

Authors: Cao, Chuanhai | Cirrito, John R. | Lin, Xiaoyang | Wang, Lilly | Verges, Deborah K. | Dickson, Alexander | Mamcarz, Malgorzata | Zhang, Chi | Mori, Takashi | Arendash, Gary W. | Holtzman, David M. | Potter, Huntington

Article Type: Research Article

Abstract: Recent epidemiologic studies suggest that caffeine may be protective against Alzheimer's disease (AD). Supportive of this premise, our previous studies have shown that moderate caffeine administration protects/restores cognitive function and suppresses brain amyloid-β (Aβ) production in AD transgenic mice. In the present study, we report that acute caffeine administration to both young adult and aged AD transgenic mice rapidly reduces Aβ levels in both brain interstitial fluid and plasma without affecting Aβ elimination. Long-term oral caffeine treatment to aged AD mice provided not only sustained reductions in plasma Aβ, but also decreases in both soluble and deposited Aβ in hippocampus …and cortex. Irrespective of caffeine treatment, plasma Aβ levels did not correlate with brain Aβ levels or with cognitive performance in individual aged AD mice. Although higher plasma caffeine levels were strongly associated with lower plasma Aβ1-40 levels in aged AD mice, plasma caffeine levels were also not linked to cognitive performance. Plasma caffeine and theophylline levels were tightly correlated, both being associated with reduced inflammatory cytokine levels in hippocampus. Our conclusion is two-fold: first, that both plasma and brain Aβ levels are reduced by acute or chronic caffeine administration in several AD transgenic lines and ages, indicating a therapeutic value of caffeine against AD; and second, that plasma Aβ levels are not an accurate index of brain Aβ levels/deposition or cognitive performance in aged AD mice. Show more

Keywords: Alzheimer's disease, amyloid-β, brain interstitial fluid, caffeine, plasma, transgenic mice

DOI: 10.3233/JAD-2009-1071

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 681-697, 2009

Authors: Tabaton, Massimo

Article Type: Article Commentary

DOI: 10.3233/JAD-2009-1089

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 699-700, 2009

Authors: Arendash, Gary W.

Article Type: Article Commentary

DOI: 10.3233/JAD-2009-1086

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 701-702, 2009