Journal of Alzheimer's Disease - Volume 24, issue 3

Authors: Piaceri, Irene | Bagnoli, Silvia | Lucenteforte, Ersilia | Mancuso, Michelangelo | Tedde, Andrea | Siciliano, Gabriele | Piacentini, Silvia | Bracco, Laura | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Short Communication

Abstract: A common polymorphism (rs3851179) in the PICALM (phosphatidylinositol-binding clathrin assembly protein) gene has been recently associated with reduced risk of developing late-onset Alzheimer's disease (LOAD). We analyzed the genotype and allele distributions of the PICALM polymorphism in 813 Italian subjects, including LOAD patients and centenarians. The segregation of the PICALM rs3851179 showed no statistically significant difference between LOAD cases and controls. The implication of a genetic variant at PICALM is confirmed for the first time, in centenarians, thus suggesting a possible role in longevity.

Keywords: Alzheimer's disease, apolipoprotein E, centenarian, genetic variation, PICALM

DOI: 10.3233/JAD-2011-101791

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 409-413, 2011

Authors: Bernardi, Livia | Anfossi, Maria | Gallo, Maura | Geracitano, Silvana | Colao, Rosanna | Puccio, Gianfranco | Curcio, Sabrina A.M. | Frangipane, Francesca | Mirabelli, Maria | Clodomiro, Alessandra | Di Lorenzo, Raffaele | Smirne, Nicoletta | Maletta, Raffaele | Iapaolo, David | Bruni, Amalia C.

Article Type: Short Communication

Abstract: Prion protein (PRNP) gene mutations have recently been associated with clinical pictures resembling Frontotemporal dementia (FTD). We describe a novel seven extra-repeat insertional mutation in the PRNP gene in a family affected by early-onset autosomal dominant FTD previously reported as caused by a PSEN1 mutation in which there was inconsistency between clinical picture and genotype. Both mutations were pathogenic and showed a variable penetrance when present separately; when occurring together, the onset was very early, within the third decade of life. Genetic screening of the PRNP gene becomes of major importance in early onset autosomal dominant dementia.

Keywords: Frontotemporal dementia, genetic polymorphism, penetrance, presenilin-1, prion protein

DOI: 10.3233/JAD-2011-101890

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 415-419, 2011

Authors: García-Mesa, Yoelvis | López-Ramos, Juan Carlos | Giménez-Llort, Lydia | Revilla, Susana | Guerra, Rafael | Gruart, Agnès | LaFerla, Frank M. | Cristòfol, Rosa | Delgado-García, José M. | Sanfeliu, Coral

Article Type: Research Article

Abstract: Physical exercise is considered to exert a positive neurophysiological effect that helps to maintain normal brain activity in the elderly. Expectations that it could help to fight Alzheimer's disease (AD) were recently raised. This study analyzed the effects of different patterns of physical exercise on the 3xTg-AD mouse. Male and female 3xTg-AD mice at an early pathological stage (4-month-old) have had free access to a running wheel for 1 month, whereas mice at a moderate pathological stage (7-month-old) have had access either during 1 or 6 months. The non-transgenic mouse strain was used as a control. Parallel animal groups were …housed in conventional conditions. Cognitive loss and behavioral and psychological symptoms of dementia (BPSD)-like behaviors were present in the 3xTg-AD mice along with alteration in synaptic function and ong-term potentiation impairment in vivo. Brain tissue showed AD-pathology and oxidative-related changes. Disturbances were more severe at the older age tested. Oxidative stress was higher in males but other changes were similar or higher in females. Exercise treatment ameliorated cognitive deterioration and BPSD-like behaviors such as anxiety and the startle response. Synaptic changes were partially protected by exercise. Oxidative stress was reduced. The best neuroprotection was generally obtained after 6 months of exercise in 7-month-old 3xTg-AD mice. Improved sensorimotor function and brain tissue antioxidant defence were induced in both 3xTg-AD and NonTg mice. Therefore, the benefits of aerobic physical exercise on synapse, redox homeostasis, and general brain function demonstrated in the 3xTg-AD mouse further support the value of this healthy life-style against neurodegeneration. Show more

Keywords: 3xTg-AD mouse, age, Alzheimer's disease, amyloid-β, behavior, cognition, electrophysiology, gender, oxidative stress, PHF-tau, voluntary exercise

DOI: 10.3233/JAD-2011-101635

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 421-454, 2011

Authors: Filippi, Massimo | Agosta, Federica

Article Type: Research Article

Abstract: Patients with Alzheimer's disease (AD) experience a brain network breakdown, reflecting disconnection at both the structural and functional system level. Resting-state (RS) functional MRI (fMRI) studies demonstrated that the regional coherence of the fMRI signal is significantly altered in patients with AD and amnestic mild cognitive impairment. Diffusion tensor (DT) MRI has made it possible to track fiber bundle projections across the brain, revealing a substantially abnormal interplay of “critical” white matter tracts in these conditions. The observed agreement between the results of RS fMRI and DT MRI tractography studies in healthy individuals is encouraging and offers interesting hypotheses to …be tested in patients with AD, aMCI, and other dementias in order to improve our understanding of their pathobiology in vivo. In this review, we describe the major findings obtained in AD using RS fMRI and DT MRI tractography, and discuss how the relationship between structure and function of the brain networks in AD may be better understood through the application of MR-based technology. This research endeavor holds a great promise in clarifying the mechanisms of cognitive decline in complex chronic neurodegenerative disorders. Show more

Keywords: Alzheimer's disease, amnestic mild cognitive impairment, diffusion tensor MRI, diffusion tensor MRI tractography, functional connectivity, resting-state functional MRI, structural connectivity

DOI: 10.3233/JAD-2011-101854

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 455-474, 2011

Authors: Bennet, Anna M. | Reynolds, Chandra A. | Eriksson, Ulrika K. | Hong, Mun-Gwan | Blennow, Kaj | Gatz, Margaret | Alexeyenko, Andrey | Pedersen, Nancy L. | Prince, Jonathan A.

Article Type: Research Article

Abstract: We performed a survey of sequence variation in a series of 20 genes involved in inflammation-related pathways for association with dementia risk in twin and unrelated case-control samples consisting in total of 1462 Swedish dementia cases and 1929 controls. For a total of 218 tested genetic markers, strong evidence was obtained implicating a region near AGER and NOTCH4 on chromosome 6p with replication across both samples and maximum combined significance at marker rs1800625 (OR = 1.37, 95% CI 1.19–1.56, p = 1.36 × 10−6 . Imputation of the associated genomic interval provided an improved signal at rs8365, near the 3′UTR …of AGER (p = 7.34 × 10−7 . The associated region extends 120 kb encompassing 11 candidate genes. While AGER encodes a key receptor for amyloid-β protein, an analysis of network context based upon genes now confirmed to contribute to dementia risk (AβPP, PSEN1, PSEN2, CR1, CLU, PICALM, and APOE) suggested strong functional coupling to NOTCH4, with no significant coupling to the remaining candidates. The implicated region occurs in the broad HLA locus on chromosome 6p, but associated markers were not in strong LD with known variants that regulate HLA gene function, suggesting that this may represent a signal distinct from immune-system pathways. Show more

Keywords: Association, dementia, gene, inflammation NOTCH4

DOI: 10.3233/JAD-2011-101848

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 475-484, 2011

Authors: Hsu, Chih-Cheng | Wahlqvist, Mark L. | Lee, Meei-Shyuan | Tsai, Hsin-Ni

Article Type: Research Article

Abstract: To determine incidence of dementia in type 2 diabetic (T2DM) patients, and whether there are adverse or favorable effects of oral agents (OA) in DM, we obtained a representative cohort of 800,000 from Taiwan's National Health Insurance database. Those who, as of on January 1, 2000, were 50 years or older and dementia free (n = 127,209) were followed until December 31, 2007, in relation to absence (n = 101,816) or presence (n = 25,393) of T2DM, and whether any OA was used. Dementia was ascertained by ICD9-CM or A-code. Dementia incidence densities (DID) and fully adjusted Cox proportional hazard …models were used to estimate association between dementia, DM, and OA. Notably, DID (per 10,000 person-years) was markedly increased with DM (without medication), compared to DM free subjects (119 versus 46). Using non-DM as reference, the adjusted hazard ratios (HRs) (95% confidence interval) for DM without and with OA were 2.41 (2.17–2.66) and 1.62 (1.49–1.77), respectively. For T2DM, compared with no medication, sulfonylureas alone reduced the HR from 1 to 0.85 (0.71–1.01), metformin alone to 0.76 (0.58–0.98), while with combined oral therapy the HR was 0.65 (0.56–0.74). Adjustments included cerebrovascular diseases so that non-stroke related dementias were found to be decreased in DM with sulfonylurea and metformin therapy. T2DM increases the risk of dementia more than 2-fold. On the other hand, sulfonylureas may decrease the risk of dementia, as does metformin; together, these 2 OAs decrease the risk of dementia in T2DM patients by 35% over 8 years. Show more

Keywords: Alzheimer's disease, anti-diabetic medication, dementia, type 2 diabetes

DOI: 10.3233/JAD-2011-101524

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 485-493, 2011

Authors: Schöll, Michael | Almkvist, Ove | Bogdanovic, Nenad | Wall, Anders | Långström, Bengt | Viitanen, Matti | Nordberg, Agneta

Article Type: Research Article

Abstract: Studies in carriers of mutations that cause early-onset familial Alzheimer's disease (eoFAD) are of significant interest. We showed previously that regional glucose hypometabolism could be detected many years before disease onset in presenilin 1 (PSEN1) mutation carriers. Here we studied four members of a family with a Met146Val PSEN1 mutation, two symptomatic carriers and two non-carriers, longitudinally with 18 F-FDG PET over a period of about two and four years, respectively. The two mutation carriers showed global cortical glucose hypometabolism over time with the most distinct decline occurring in the posterior cingulate, the parietal and parietotemporal cortex, which was also …observed when compared with a group of 23 healthy controls and a group 27 sporadic Alzheimer's disease (sAD) patients. This decline correlated with cognitive deterioration over time as measured by neuropsychological tests. Postmortem examination of brain tissue revealed substantially elevated levels of AD type neuropathology in terms of neuritic plaques and neurofibrillary tangles in the two mutation carriers compared with a reference group of sAD patients. In the mutation carriers, the amount of neuritic plaques but not neurofibrillary tangles correlated hereby significantly with regional glucose metabolism as measured by 18 F-FDG on the last scanning occasions, which were performed four and approximately five years before death, respectively. We here show that FDG PET can depict in vivo the aggressive disease progression in eoFAD mutation carriers in relationship to neuropathology. Show more

Keywords: Early-onset familial Alzheimer's disease, FDG, longitudinal studies, neuritic plaques, neurofibrillary tangles, postitron emission tomography, postmortem pathology, presenilin 1

DOI: 10.3233/JAD-2011-101563

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 495-506, 2011

Authors: Igarashi, Miki | Ma, Kaizong | Gao, Fei | Kim, Hyung-Wook | Rapoport, Stanley I. | Rao, Jagadeesh S.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by brain deposition of senile (neuritic) plaques containing amyloid-β, neurofibrillary tangles, synaptic loss, neuroinflammation, and overexpression of arachidonic acid (AA, 20:4n-6) metabolizing enzymes. Lipid concentration changes have been reported in different brain regions, but often partially or as a percent of the total concentration. In this study, we measured absolute concentrations (per gram wet weight) of a wide range of lipids in postmortem prefrontal cortex (Brodmann area 9) from 10 AD patients and 9 non-AD controls. Mean total brain lipid, phospholipid, cholesterol, and triglyceride concentrations did not differ significantly between AD …and controls. There was a significant 73% decrease in plasmalogen choline, but no difference in other measured phospholipids. Fatty acid concentrations in total phospholipid did not differ from control. However, docosahexaenoic acid (DHA, 22:6n-3) was reduced in ethanolamine glycerophospholipid and choline glycerophospholipid, but increased in phosphatidylinositol. AA was reduced in choline glycerophospholipid, but increased in phosphatidylinositol, while docosatetraenoic acid (22:4n-6), an AA elongation product, was reduced in total brain lipid, cholesteryl ester and triglyceride. These lipid changes, which suggest extensive membrane remodeling, may contribute to membrane instability and synaptic loss in AD and reflect neuroinflammation. Show more

Keywords: Alzheimer's disease, arachidonic, brain, cholesteryl ester, docosahexaenoic acid, lipid, phospholipid, plasmalogen, postmortem

DOI: 10.3233/JAD-2011-101608

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 507-517, 2011

Authors: Hong, Yun Jeong | Yoon, Bora | Shim, Yong S. | Cho, A-Hyun | Shin, Hae-Eun | Kim, Yeong-In | Kim, Sang Yun | Yang, Dong Won

Article Type: Research Article

Abstract: Few studies have investigated the apolipoprotein E (APOE) ε4 allele status of dementia patients with severe white matter hyperintensities (WMH). In this study, we aimed to characterize the APOE epsivlon genotypes and clinical features of dementia patients with severe WMH. Four hundred and thirty nine patients with dementia and 152 subjects with normal cognition (NC) were recruited from multiple centers in Korea, known as the Clinical Research Center for Dementia of South Korea (CREDOS), since November 2005. The WMH were rated using the scale that had been developed by the CREDOS study. Dementia patients with minimal WMH were considered to …have Alzheimer's disease (AD) without WMH (AD-WMH: 325), and those with severe WMH were considered to have Subcortical Ischemic Vascular Dementia (SIVD: 50) or AD with severe WMH (AD+WMH: 64). Comparisons of APOE ε4 allelic prevalence were performed using chi-square analysis. The APOE ε4 allele was more prevalent in those with AD than in those with SIVD and NC (p < 0.001). It was not more prevalent in those with SIVD than in those with NC (p = 0.169). APOE ε4 allele status in AD+WMH did not differ from that in AD-WMH (p = 0.625). The APOE ε4 allele was more prevalent in those with AD than in those with SIVD. APOE ε4 may not be associated with SIVD although it is one of the vascular risk factors. Show more

Keywords: Alzheimer's disease, apolipoprotein E, vascular dementia, white matter hyperintensities

DOI: 10.3233/JAD-2011-101611

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 519-524, 2011

Authors: Yu, Guang | Li, Yi | Tian, Qing | Liu, Rong | Wang, Qun | Wang, Jian-Zhi | Wang, Xiaochuan

Article Type: Research Article

Abstract: The Chinese herb berberine has versatile health effects. Recent reports indicate that berberine has the potential to prevent and treat Alzheimer's disease (AD). In the present study, we employed tau-expressing HEK293 cells (HEK293/tau) treated with calyculin-A as a cellular model to investigate the roles of berberine in cell viability, tau phosphorylation, and oxidative stress. We found a significant reduction of calyculin A-induced tau hyperphosphorylation at Ser198/199/202, Ser396, Ser404, Thr205, and Thr231 24 h after treatment with 20 μg/ml berberine. Berberine also restored protein phosphates 2A activity and reversed glycogen synthase kinase-3β (GSK-3β) activation, as determined by phosphatase activity assay and …GSK-3β phosphorylation at Tyr216 and Ser9, respectively. Furthermore, berberine reversed both the increase of malondialdehyde and the decrease of superoxide dismutase activity induced by calyculin A, indicating its role in anti-oxidative stress. Our findings suggest that berberine may be a potential therapeutic drug for AD. Show more

Keywords: Alzheimer's disease, berberine, GSK-3β, PP2A, tau hyperphosphorylation

DOI: 10.3233/JAD-2011-101779

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 525-535, 2011