Journal of Alzheimer's Disease - Volume 19, issue 3

Authors: DeMichele-Sweet, Mary Ann | Sweet, Robert A.

Article Type: Review Article

Abstract: In and of itself, late-onset Alzheimer's disease (AD) can be a devastating illness. However, a sub-group of AD patients develop psychosis as the disease progresses. These patients have an added burden of greater cognitive impairment, higher rates of institutionalization, and higher mortality than AD patients without psychosis. While the etiopathogenesis such as psychosis in AD (AD+P) is not known, mounting evidence accrued over the past ten years indicates that AD+P represents a distinct phenotype with a genetic basis. Elucidating the genetic mechanism of AD+P is crucial if better pharmaceutical treatments are to be developed for these patients. The goal of …this review is to summarize what is currently known regarding the genetic basis of psychosis in AD. Specific attention is given to familial aggregation and heritability, linkage to chromosomal loci, and associations of candidate genes of APOE and the monoamine neurotransmitter system. An erratum for this article can be found in Journal of Alzheimer's Disease 20(4), 2010, p. 1263. https://dx.doi.org/10.3233/JAD-2010-1426 Show more

Keywords: APOE, association analysis, COMT, dopamine, heritability, linkage analysis, NRG1, serotonin

DOI: 10.3233/JAD-2010-1274

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 761-780, 2010

Authors: Kaufman, Liam D. | Pratt, Jay | Levine, Brian | Black, Sandra E.

Article Type: Review Article

Abstract: The number of people living with Alzheimer's disease (AD), the major cause of dementia, is projected to increase dramatically over the next few decades, making the search for treatments and tools to measure the progression of AD increasingly urgent. The antisaccade task, a hands- and language-free measure of inhibitory control, has been utilized in AD as a potential diagnostic test. While antisaccades do not appear to differentiate AD from healthy aging better than measures of episodic memory, they may still be beneficial. Specifically, antisaccades may provide not only a functional index of the Dorsolateral Prefrontal Cortex (DLPFC), which is damaged …in the later stages of AD, but also a tool for monitoring the progression of AD. Further work is required to: 1) strengthen the link between antisaccade errors, in AD, with the DLPFC; 2) insure that antisaccade errors do not result from memory, visuospatial, or other deficits associated with AD; and 3) further validate the clinical analogue of the antisaccade task. Show more

Keywords: Alzheimer's disease, antisaccades, dementia, dorsolateral prefrontal cortex

DOI: 10.3233/JAD-2010-1275

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 781-793, 2010

Authors: Choi, Roy C.Y. | Zhu, Judy T.T. | Leung, K. Wing | Chu, Glanice K.Y. | Xie, Heidi Q. | Chen, Vicky P. | Zheng, Ken Y.Z. | Lau, David T.W. | Dong, Tina T.X. | Chow, Peter C.Y. | Han, Yi-Fan | Wang, Zheng-Tao | Tsim, Karl W.K.

Article Type: Research Article

Abstract: A Radix Notoginseng flavonol glycoside (RNFG), quercetin 3-O-β-D-xylopyranosyl-β-D-galactopyranoside, was isolated from roots of Panax notoginseng. Among different biological properties tested, RNFG possessed a strong activity in preventing amyloid-β (Aβ)-induced cell death. In an in vitro assay, RNFG inhibited the aggregation of Aβ in a dose-dependent manner. Moreover, application of RNFG in cultured cortical neurons, or PC12 cells, reduced the Aβ-induced cell death in time- and dose-dependent manners, with the suppression of Aβ-induced DNA fragmentation and caspase-3 activation. In cultured neurons, the pre-treatment of RNFG abolished the increase of Ca2+ mobilization triggered by Aβ. The neuroprotective properties of RNFG required …a specific sugar attachment within the main chemical backbone because the flavonol backbone by itself did not show any protective effect. In memory impairment experiments using the passive avoidance task, the administration of RNFG reduced brain damage in scopolamine-treated rats. These results therefore reveal a novel function of Radix Notoginseng and its flavonol glycoside that could be very useful in developing food supplements for the prevention, or potential treatment, of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, Chinese medicine, flavonol glycoside, neuroprotection, Panax notoginseng

DOI: 10.3233/JAD-2010-1293

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 795-811, 2010

Authors: Ho, Yuen-Shan | Yu, Man-Shan | Yang, Xi-Fei | So, Kwok-Fai | Yuen, Wai-Hung | Chang, Raymond Chuen-Chung

Article Type: Research Article

Abstract: Previous clinical and epidemiological studies have suggested that elevated plasma homocysteine (Hcy) levels increased the risk of Alzheime's disease (AD). Although the underlying mechanisms of its toxicity are elusive, it has been shown that Hcy damages neurons by inducing apoptosis, DNA fragmentation, and tau hyperphosphorylation. Wolfberry (Lycium barbarum) is a fruit that is known for its eye-protective and anti-aging properties in Asian countries. Previous studies from our laboratory have demonstrated that polysaccharides derived from wolfberry (LBA) have the ability to protect neurons from amyloid-β (Aβ) peptide neurotoxicity. We hypothesize that the neuroprotective effects of wolfberry is not limited to Aβ …and can also provide protection against other AD risk factors. In this study, we aim to elucidate the neuroprotective effects of wolfberry against Hcy-induced neuronal damage. Our data showed that LBA treatment significantly attenuated Hcy-induced neuronal cell death and apoptosis in primary cortical neurons as demonstrated by LDH and caspase-3 like activity assay. LBA also significantly reduced Hcy-induced tau phosphorylation at tau-1 (Ser198/199/202), pS396 (Ser396), and pS214 (Ser214) epitopes as well as cleavage of tau. At the same time, we also found that the phosphorylation level of p-GSK3β (Ser9/Tyr 216) remained unchanged among different treatment groups at all detected time points. LBA treatment suppressed elevation of both p-ERK and p-JNK. In summary, our data demonstrated that LBA exerted neuroprotective effects on cortical neurons exposed to Hcy. Therefore, LBA has the potential to be a diseasemodifying agent for the prevention of AD. Show more

Keywords: Apoptosis, homocysteine, neuroprotection, tau phosphorylation, Wolfberry

DOI: 10.3233/JAD-2010-1280

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 813-827, 2010

Authors: Ji, Lina | Chauhan, Abha | Chauhan, Ved

Article Type: Research Article

Abstract: We have previously reported that gelsolin, an actin binding protein, regulates the fibrillization of amyloid-β protein. We report here that the expression of cytoplasmic gelsolin (cgelsolin) was upregulated in a concentration-dependent manner when SH-SY5Y, PC-12, and HEK-293 cells were subjected to oxidative stress by treatment with hydrogen peroxide (H2 O2 ). Further studies were done to elucidate the mechanism involved in the regulation of c-gelsolin expression in cells. Pretreatment of cells with cycloheximide (an inhibitor of protein synthesis) resulted in significant inhibition of H2 O2 -induced c-gelsolin expression, suggesting the possible de novo synthesis of c-gelsolin in cells. Staurosporine, a …potent inhibitor of a variety of protein kinases including protein kinase C (PKC), also blocked the H2 O2 -induced expression of cgelsolin. However, both H2 O2 and staurosporine activated the mitogen-activated protein kinases (MAPKs), i.e., c-Jun N-terminal kinase, P38, and extracellular signal-regulated kinase. Pretreatment of cells with Calphostin C, an inhibitor of PKC, blocked the upregulation of cgelsolin induced by H2 O2 , while specific inhibitors of MAPKs had no effect on c-gelsolin expression, suggesting that MAPKs may not be involved in H2 O2 -mediated upregulation of cgelsolin. On the other hand, phorbol-12-myristate-13-acetate, an activator of PKC, induced the expression of c-gelsolin. Our studies indicate that c-gelsolin is upregulated in cells under oxidative stress, and PKC is involved in its upregulation. It is suggested that activators of PKC that induce gelsolin expression may have therapeutic significance in Alzheimer's disease. Show more

Keywords: Gelsolin, mitogen-activated protein kinases, oxidative stress, protein kinase C

DOI: 10.3233/JAD-2010-1281

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 829-838, 2010

Authors: Souza-Talarico, Juliana N. | Chaves, Eliane C. | Lupien, Sonia J. | Nitrini, Ricardo | Caramelli, Paulo

Article Type: Research Article

Abstract: An inverted U-shape function between cortisol levels and memory performance has been reported in studies on both young animals and humans. Yet little is known about this relationship in normal aging or in older subjects with cognitive impairment. This issue is particularly significant since increased levels of cortisol have been reported in Alzheimer's disease (AD). The present study examined the association between cortisol levels and visual memory performance in healthy subjects as well as in individuals presenting mild cognitive impairment (MCI) or AD. Salivary cortisol was measured in 40 healthy elderly subjects, 31 individuals with amnestic MCI, and 40 subjects …with mild probable AD. Memory performance was evaluated using the Brief Cognitive Screening Battery. Higher cortisol levels were associated with better memory performance in healthy elderly (p=0.005), while higher cortisol levels were correlated with poorer memory performance in MCI subjects (p=0.011). No correlation between cortisol and memory was found in the AD group (p > 0.05). These results suggest that the relationship between cortisol levels and memory performance in the aging process could vary according to the presence or absence of cognitive impairment. Show more

Keywords: Aging, Alzheimer's disease, cognition, glucocorticoids, memory, mild cognitive impairment

DOI: 10.3233/JAD-2010-1282

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 839-848, 2010

Authors: Zhang, Lan-Jiang | Xiao, Yan | Qi, Xiao-Lan | Shan, Ke-Ren | Pei, Jin-Jing | Kuang, Shi-Xiang | Liu, Fang | Guan, Zhi-Zhong

Article Type: Research Article

Abstract: The aim of the study is to investigate the cholinergic deficit in Alzheimer's disease (AD) and identify candidate blood biomarkers for the diagnosis of the disease. Twenty-nine elderly Chinese diagnosed with AD and 33 age-matched controls were selected. The activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in plasma were detected by a spectrophotometric method, and the mRNA levels of α4 and β2 nicotinic acetylcholine receptor (nAChR) subunits in blood leukocytes were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). The results showed that AChE activity in plasma was significantly lower in the AD group than in normal controls, while BuChE activity …did not show any differences between AD and controls; mRNA levels of both α4 and β2 nAChR subunits in blood leukocytes were significantly lower in the AD group than in controls. The AChE activity and the mRNA levels of α4 and β2 nAChR subunits in the AD patients were also significantly correlated with cognitive test scores. No differences of AChE in plasma or α4 and β2 nAChR subunits in blood leukocytes were detected between smoking and non-smoking subjects. The results indicated that the decreases in the activity of AChE and in the mRNA levels of nAChR α4 and β2 subunits from the peripheral blood of patients with AD might serve as supplementary indicators for the clinical diagnosis of AD. Show more

Keywords: Acetylcholinesterase, Alzheimer's disease, butyrylcholinesterase, nicotinic acetylcholine receptors

DOI: 10.3233/JAD-2010-1283

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 849-858, 2010

Authors: Babiloni, Claudio | Frisoni, Giovanni B. | Vecchio, Fabrizio | Pievani, Michela | Geroldi, Cristina | De Carli, Charles | Ferri, Raffaele | Vernieri, Fabrizio | Lizio, Roberta | Rossini, Paolo M.

Article Type: Research Article

Abstract: We tested the hypothesis that global functional coupling of resting cortical electroencephalographic (EEG) rhythms is abnormal in amnesic mild cognitive impairment (MCI) patients with remarkable lesions along the cholinergic white-matter tracts. We used the eyes-closed resting EEG data (10–20 montage) of the same groups of 28 healthy elderly (Nold) and 57 MCI subjects of a previous reference study. The estimation of the cholinergic lesion was performed with a validated semi-automatic algorithm based on fluid-attenuated inversion recovery sequences on MRI. The MCI patients were divided into groups of high (MCI+; n=28) and low (MCI-; n=29) cholinergic damage. EEG rhythms of interest …were delta (2–4 Hz), theta (4–8 Hz), alpha1 (8–10.5 Hz), alpha2 (10.5–13 Hz), beta1 (13–20 Hz), beta2 (20–30 Hz), and gamma (30– 40 Hz). The global functional coupling of the EEG rhythms was indexed computing the spectral coherence between each electrode and the other 18 electrodes ("electrode" coherence) and then averaging the "electrode" coherence of all 19 electrodes (total coherence). Total coherence of alpha1 rhythms was highest in the Nold, intermediate in the MCI-, and lowest in the MCI+ groups. Furthermore, the alpha1 total coherence was negatively correlated to (moderate to high) cholinergic lesion across the MCI subjects. In conclusion, damage to the cholinergic system is associated with alterations of the functional global coupling of resting alpha rhythms. Show more

Keywords: Amnesic mild cognitive impairment, cholinergic system, EEG rhythms, electroencephalography, magnetic resonance imaging, Mini Mental State Examination, spectral coherence, total coherence, white-matter vascular lesion

DOI: 10.3233/JAD-2010-1290

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 859-871, 2010

Authors: Gómez-Tortosa, Estrella | Barquero, Sagrario | Barón, Manuel | Gil-Neciga, Eulogio | Castellanos, Fernando | Zurdo, Martín | Manzano, Sagrario | Muñoz, David G. | Jiménez-Huete, Adolfo | Rábano, Alberto | Sainz, M. José | Guerrero, Rosa | Gobernado, Isabel | Pérez-Pérez, Julián | Jiménez-Escrig, Adriano

Article Type: Research Article

Abstract: We describe the clinical phenotype of nine kindred with presenile Alzheimer's disease (AD) caused by different presenilin 1 (PS1) point mutations, and compare them with reported families with mutations in the same codons. Mutations were in exon 4 (Phe105Val), exon 5 (Pro117Arg, Glu120Gly), exon 6 (His163Arg), exon 7 (Leu226Phe), exon 8 (Val261Leu, Val272Ala, Leu282Arg), and exon 12 (Ile439Ser). Three of these amino acid changes (Phe105Val, Glu120Gly, and Ile439Ser) had not been previously reported. Distinct clinical features, including age of onset, symptoms and signs associated with the cortical-type dementia and aggressiveness of the disease, characterized the different mutations and were quite …homogeneous across family members. Age of onset fell within a consistent range: some mutations caused the disease in the thirties (P117R, L226F, V272A), other in the forties (E120G, H163R, V261L, L282R), and other in the fifties (F105V, I439S). Associated features also segregated with specific mutations: early epileptic activity (E120G), spastic paraparesis (V261L), subcortical dementia and parkinsonism (V272A), early language impairment, frontal signs, and myoclonus (L226F), and late myoclonus and seizures (H163R, L282R). Neurological deterioration was particularly aggressive in PS1 mutations with earlier age of onset such as P117R, L226F, and E120G. With few exceptions, a similar clinical phenotype was found in families reported to have either the same mutation or different amino acid changes in the same codons. This series points to a strong influence of the specific genetic defect in the development of the clinical phenotype. Show more

Keywords: early onset, familial Alzheimer's disease, mutations, presenilin 1

DOI: 10.3233/JAD-2010-1292

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 873-884, 2010

Authors: Tizon, Belen | Ribe, Elena M. | Mi, Weiqian | Troy, Carol M. | Levy, Efrat

Article Type: Research Article

Abstract: Multiple studies suggest that cystatin C (CysC) has a role in Alzheimer's disease (AD) and a decrease in CysC secretion is linked to the disease in patients with a polymorphism in the CysC gene. CysC binds amyloid-β (Aβ) and inhibits formation of Aβ fibrils and oligomers both in vitro and in mouse models of amyloid deposition. Here we studied the effect of CysC on cultured primary hippocampal neurons and a neuronal cell line exposed to either oligomeric or fibrillar cytotoxic forms of Aβ. The extracellular addition of the secreted human CysC together with preformed either oligomeric or fibrillar Aβ increased …cell survival. While CysC inhibits Aβ aggregation, it does not dissolve preformed Aβ fibrils or oligomers. Thus, CysC has multiple protective effects in AD, by preventing the formation of the toxic forms of Aβ and by direct protection of neuronal cells from Aβ toxicity. Therapeutic manipulation of CysC levels, resulting in slightly higher concentrations than physiological could protect neuronal cells from cell death in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, cystatin C, neurodegeneration, neuroprotection

DOI: 10.3233/JAD-2010-1291

Citation: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 885-894, 2010