Journal of Alzheimer's Disease - Volume 19, issue 4

Authors: Daffner, Kirk R.

Article Type: Review Article

Abstract: Promoting successful cognitive aging is a topic of major importance to individuals and the field of public health. This review presents a coherent framework not only for evaluating factors, protective activities, and enhancing agents that have already been proposed, but also ones that will be put forward in the future. The promotion of successful cognitive aging involves the dual goals of preventing loss of information processing capacity and cognitive reserve, and enhancing brain capacity and cognitive reserve. Four major lines of evidence are available for evaluating whether a proposed factor promotes successful cognitive aging: 1) epidemiologic/cohort studies; 2) animal/basic science …studies; 3) human “proof-of-concept” studies; and 4) human intervention studies. Each line of evidence has advantages and limitations that will be discussed. Through illustrative examples, we trace the ways in which each method informs us about the potential value of several proposed factors. Currently, lines of converging evidence allow the strongest case to be made for physical and cognitively stimulating activities. Although epidemiological data seem to favor the use of statins to lower the risk of dementia, more definitive recommendations await further randomized controlled studies. There is presently no clear evidence that antioxidants or Ginkgo biloba promote successful cognitive aging. The impact of resveratrol, fish oil, and a long list of other proposed agents needs to be determined. Clinicians remain well-positioned to identify and aggressively treat vascular risk factors, diabetes, sleep disorders, and other conditions that may reduce brain capacity, and to encourage activities that can build cognitive reserve. Show more

Keywords: Clinical research methods, cognition, cognitive reserve, dementia risk factors, neuroprotection, successful aging

DOI: 10.3233/JAD-2010-1306

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1101-1122, 2010

Authors: Ramesh, Balenahalli N. | Rao, T.S. Sathyanarayana | Prakasam, Annamalai | Sambamurti, Kumar | Rao, K.S. Jagannatha

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a complex neurological disorder resulting from both genetic and environmental factors with the latter being particularly important for the sporadic form of the disease. As such, diets rich in saturated fatty acids and alcohol, and deficient in antioxidants and vitamins appear to promote the onset of the disease, while diets rich in unsaturated fatty acids, vitamins, antioxidants, and wine likely suppress its onset. In addition, evidence suggests that diets rich in polyphenols and some spices suppress the onset of AD by scavenging free radicals and preventing oxidative damage. Metal ions are known to catalyze the production …of free radicals and induce mental retardation or dementia, and several studies have also identified metals such as Pb, Fe, Al, Cu, and Zn in AD pathogenesis. While specific metal chelators have been tested for therapy, they have not been very successful, probably due to their late administration, i.e., after brain damage has been triggered. Since several dietary polyphenols are known to chelate metals, their routine use may also be protective against the onset of AD. In this review, we summarize beneficial dietary techniques in the fight against AD. Show more

Keywords: Antioxidants, caloric restriction, diet, homocysteine, lipid, neurodegeneration, nutrients, oxidative stress, polyphenols, vitamins

DOI: 10.3233/JAD-2010-1312

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1123-1139, 2010

Authors: Shen, Liang | Ji, Hong-Fang

Article Type: Letter

DOI: 10.3233/JAD-2010-1307

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1141-1142, 2010

Authors: Comi, Cristoforo | Carecchio, Miryam | Chiocchetti, Annalisa | Nicola, Stefania | Galimberti, Daniela | Fenoglio, Chiara | Cappellano, Giuseppe | Monaco, Francesco | Scarpini, Elio | Dianzani, Umberto

Article Type: Short Communication

Abstract: Inflammation is believed to play a role in Alzheimer's disease (AD). Osteopontin (OPN) is a molecule involved in macrophage recruitment and activation and implicated in neurodegeneration. In order to elucidate the role of OPN in AD, we evaluated its levels in serum and cerebrospinal fluid (CSF) of 67 AD patients, 46 frontotemporal dementia (FTD) patients, and 69 controls. We found that OPN levels: i) are significantly increased in the CSF of AD patients; ii) correlate with MMSE score; and iii) are higher in the early disease phases (⩽ 2 years). These findings support a role of OPN in AD pathogenesis.

Keywords: Disease progression, early Alzheimer's disease, Eta-1, microglia, neuroinflammation

DOI: 10.3233/JAD-2010-1309

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1143-1148, 2010

Authors: VanFossen, Brian T. | Watson, G. Stennis | Baker, Laura D. | Rhoads, Kristoffer W. | Cholerton, Brenna A. | Reger, Mark A. | Plymate, Stephen R. | Schellenberg, Gerald | Craft, Suzanne

Article Type: Short Communication

Abstract: The present study examined the relationships among statin use, APOE genotype, and insulin resistance as measured by the homeostasis model assessment of insulin resistance (HOMA-IR) in healthy older adults. APOE ε4- (i.e., not having an ε4 allele) statin users had higher HOMA-IR values compared with ε4+/statin users (p = 0.0169), and with non-users who were ε4- (p = 0.0003) or ε4+ (p = 0.0006). These results suggest that statin use may modulate insulin levels for individuals without an APOE ε4 allele.

Keywords: Alzheimer's disease, dementia, diabetes, insulin, statin

DOI: 10.3233/JAD-2010-1319

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1149-1153, 2010

Authors: Greco, Steven J. | Bryan, Kathryn J. | Sarkar, Sraboni | Zhu, Xiongwei | Smith, Mark A. | Ashford, J. Wesson | Johnston, Jane M. | Tezapsidis, Nikolaos | Casadesus, Gemma

Article Type: Research Article

Abstract: We have previously reported anti-amyloidogenic effects of leptin using in vitro and in vivo models and, more recently, demonstrated the ability of leptin to reduce tau phosphorylation in neuronal cells. The present study examined the efficacy of leptin in ameliorating the Alzheimer's disease (AD)-like pathology in 6-month old CRND8 transgenic mice (TgCRND8) following 8 weeks of treatment. Leptin-treated transgenic mice showed significantly reduced levels of amyloid-β (Aβ)1–40 in both brain extracts (52% reduction, p = 0.047) and serum (55% reduction, p = 0.049), as detected by ELISA, and significant reduction in amyloid burden (47% reduction, p = 0.041) in …the hippocampus, as detected by immunocytochemistry. The decrease in the levels of Aβ in the brain correlated with a decrease in the levels of C99 C-terminal fragments of the amyloid-β protein precursor, consistent with a role for β -secretase in mediating the effect of leptin. In addition, leptin-treated TgCRND8 mice had significantly lower levels of phosphorylated tau, as detected by AT8 and anti-tau-Ser396 antibodies. Importantly, after 4 or 8 weeks of treatment, there was no significant increase in the levels of C-reactive protein, tumor necrosis factor-α, and cortisol in the plasma of leptin-treated TgCRND8 animals compared to saline-treated controls, indicating no inflammatory reaction. These biochemical and pathological changes were correlated with behavioral improvements, as early as after 4 weeks of treatment, as recorded by a novel object recognition test and particularly the contextual and cued fear conditioning test after 8 weeks of treatment. Leptin-treated TgCRND8 animals significantly outperformed saline-treated littermates in these behavioral tests. These findings solidly demonstrate the potential for leptin as a disease modifying therapeutic in transgenic animals of AD, driving optimism for its safety and efficacy in humans. Show more

Keywords: Alzheimer's disease, amyloid-β, CRND8, leptin, tau

DOI: 10.3233/JAD-2010-1308

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1155-1167, 2010

Authors: Bettens, Karolien | Brouwers, Nathalie | Van Miegroet, Helen | Gil, Ana | Engelborghs, Sebastiaan | De Deyn, Peter P. | Vandenberghe, Rik | Van Broeckhoven, Christine | Sleegers, Kristel

Article Type: Research Article

Abstract: Replication of genetic association findings in independent studies represents an important validation tool in the search for susceptibility genes for complex diseases such as Alzheimer's disease (AD). In a well-characterized memory-clinic based study comprising 1078 unrelated AD patients and 652 control individuals, we set out to replicate previously reported genome-wide association of four novel risk SNPs with AD and onset age, with first stage p-values ranging from 0.001 to 0.000004. We obtained evidence for association between rs179943, an intronic SNP in ATXN1 at 6p22.3, and affection status (OR = 0.63 (95% CI = 0.44–0.90; nominal p = 0.01)). Overall, our …data provided independent support for association of at least one chromosomal locus with AD and warranted a more in-depth investigation of these regions for possible underlying functional variants. Show more

Keywords: Alzheimer dementia, genome-wide association, onset age, replication

DOI: 10.3233/JAD-2010-1310

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1169-1175, 2010

Authors: Suszynska, Joanna | Tisonczyk, Joanna | Lee, Hyoung-gon | Smith, Mark A. | Jakubowski, Hieronim

Article Type: Research Article

Abstract: Elevated plasma homocysteine (Hcy) is a risk factor for Alzheimer's disease (AD). Bleomycin hydrolase (BLH), a thiol-dependent enzyme that has Hcy-thiolactonase (HTase) and aminopeptidease (APase) activities, has also been implicated in Alzheimer's disease (AD). In order to examine its role in AD, BLH activities were measured in postmortem brain tissue from twelve AD patients and twelve control patients who died from non-neurological causes. We found that HTase and APase activities in human brain extracts were strongly correlated and sensitive to the thiol reagent iodoacetamide, indicating that they are associated with BLH. Both activities were significantly decreased in brain tissue extracts …from AD patients relative to controls (7.6 ± 4.2 vs. 13.5 ± 5.5 units, p = 0.003 for HTase, and 3.82 ± 1.27 vs. 5.33 ± 1.68 units, p = 0.010 for APase). HTase and APase activities were positively correlated with N-linked protein Hcy, but not with tHcy, in AD and control brains. Levels of brain total Hcy and N-linked protein Hcy did not differ between AD cases and controls. These results suggest that diminished functional BLH activity could contribute to the pathology of AD. Show more

Keywords: Alzheimer's disease, aminopeptidase, bleomycin hydrolase, homocysteine-thiolactonase

DOI: 10.3233/JAD-2010-1311

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1177-1183, 2010

Authors: Humbert, Ianessa A. | McLaren, Donald G. | Kosmatka, Kris | Fitzgerald, Michele | Johnson, Sterling | Porcaro, Eva | Kays, Stephanie | Umoh, Eno-Obong | Robbins, JoAnne

Article Type: Research Article

Abstract: The goal of this study was to determine whether functional changes in cortical control of swallowing are evident in early Alzheimer's disease (AD), before dysphagia (swallowing impairment) is evident. Cortical function was compared between an early AD group and a group of age-matched controls during swallowing. Swallowing oropharyngeal biomechanics examined from videofluoroscopic recordings were also obtained to more comprehensively characterize changes in swallowing associated with early AD. Our neuroimaging results show that the AD group had significantly lower Blood-Oxygen-Level-Dependent (BOLD) response in many cortical areas that are traditionally involved in normal swallowing (i.e., pre and postcentral gyri, Rolandic and frontal …opercula). There were no regions where the AD group showed more brain activity than the healthy controls during swallowing, and only 13% of all active voxels were unique to the AD group, even at this early stage. This suggests that the AD group is not recruiting new regions, nor are they compensating within regions that are active during swallowing. In videofluoroscopic measures, the AD group had significantly reduced hyo-laryngeal elevation than the controls. Although, swallowing impairment is usually noted in the late stages of AD, changes in cortical control of swallowing may begin long before dysphagia becomes apparent. Show more

Keywords: Alzheimer's disease, deglutition, neuroimaging, neurophysiology, videofluoroscopy

DOI: 10.3233/JAD-2010-1316

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1185-1197, 2010

Authors: Zimmermann, R. | Beck, Georg | Knispel, Sabine | Maler, Juan Manuel | Weih, Markus | Wiltfang, Jens | Kornhuber, Johannes | Lewczuk, Piotr

Article Type: Research Article

Abstract: Neurochemical Dementia Diagnostics (NDD), i.e., analysis of the cerebrospinal fluid (CSF) concentrations of amyloid-β peptides and tau/phospho-tau proteins plays important role in the diagnosis of neurodegeneration and dementias. Several studies show alterations of these biomarkers in Alzheimer's disease (AD), however, only a few reports address alterations of other CSF biomarkers (albumin and immunoglobulins' quotients, cell count, lactate concentration, etc.) in the pathophysiology and diagnostic procedures of dementias. Therefore, we analyzed these biomarkers in patients diagnosed for dementia syndromes and carefully characterized with the state-of-the-art NDD analysis: Aβ1–42 , Aβx–42 , Aβx–42/x–40 ratio, tau, and ptau181. We found intrathecal IgG …synthesis in 5 out of 112 patients showing alterations of the NDD biomarkers, and in four out of these five subjects, we could not find any satisfying reason for the intrathecal humoral response. In 25.9% of the patients with altered NDD biomarkers, we found an increased albumin quotient indicating a dysfunction of the blood-CSF barrier; however a similar figure of 25.2% was found in the group of patients without alterations in the NDD. Our findings suggest that at least some patients with increased CSF concentrations of tau/ptau proteins and decreased concentrations of Aβ42 peptides show simultaneously CSF alterations found otherwise in neuroinflammatory processes. This, in turn, suggests that extended diagnosis should be performed in patients with “isolated” alterations of NDD biomarkers or intrathecal immunoglobulin synthesis. Show more

Keywords: Amyloid-β, cerebrospinal fluid, dementia, neurodegeneration, neuroimmunology, tau

DOI: 10.3233/JAD-2010-1313

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1199-1203, 2010