Journal of Alzheimer's Disease - Volume 30, issue 1

Authors: Zheng, Hailin | Amit, Tamar | Bar-Am, Orit | Fridkin, Mati | Youdim, Moussa B.H. | Mandel, Silvia A.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a multifactorial syndrome involving a complex array of different, while related, factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel hybrid molecules with multimodal activity, including: i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity; ii) HLA20, a brain permeable metal chelator with neuroprotective activity; iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity; iv) M30D, an AChE and MAO-A and -B inhibitor with …site-activated chelating and neuroprotective activity; and v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency and AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including modulation of amyloid-β and amyloid-β protein precursor expression/processing; induction of cell cycle arrest; inhibition of neuronal death markers; and upregulation of neurotrophic factors, as well as activation of protein kinase signaling pathways. Show more

Keywords: AChE-MAO-A and -B inhibitors, Alzheimer's disease, M30, multitarget chelators, site-activated

DOI: 10.3233/JAD-2012-120013

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 1-16, 2012

Authors: Serot, Jean-Marie | Zmudka, Jadwiga | Jouanny, Pierre

Article Type: Review Article

Abstract: According to the amyloid theory, the appearance of amyloid-β (Aβ) deposits represents a pivotal event in late onset Alzheimer's disease (LOAD). Physiologically, Aβ42 monomers are cleaned by capillary resorption, enzymatic catabolism, and cerebrospinal fluid (CSF) transport. Factors that promote the oligomerization of Aβ42 must be specified. In vitro, these monomers spontaneously form neurotoxic oligomers whose rate increases with time suggesting that the stasis of CSF favors the oligomerization. In animals, experimental hydrocephalus generates CSF stasis followed by the appearance of amyloid deposits. In normal pressure hydrocephalus, amyloid deposits are common, especially in elderly patients, and the turnover decline …has the same order of magnitude as in AD. In this disease, the effects of CSF stasis are potentiated by the decline in the ability of CSF to inhibit the formation of oligomers. CSF originates from choroid plexus (CP). In LOAD, the functions of secretion, synthesis, and transport of CP are impaired and this is related to morphological modifications. These impairments favor the decrease of CSF turnover, the diminished levels of transthyretin, a sequestering protein synthesized by CP, and the oligomerization of Aβ42 . They are potentiated by a reduced enzymatic catabolism and a decreased capillary reabsorption of Aβ42 , both alterations being related to age. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, choroid plexus, turnover

DOI: 10.3233/JAD-2012-111964

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 17-26, 2012

Authors: Shea, Thomas B. | Rogers, Eugene | Remington, Ruth

Article Type: Research Article

Abstract: Alzheimer's disease (AD) has no cure or nullifying pharmacological interventions. Nutritional supplementation represents a systemic approach that in some studies has provided benefit and has augmented pharmacological approaches. However, additional studies report no benefit of supplementation. We review herein how studies of nutrition on dementia, including those combining nutrition and dementia, are inherently compromised. We also review studies with mice, which demonstrate that nutritional supplementation can alleviate multiple genetic risk factors for AD. An individual diagnosed with AD has by definition undergone considerable cognitive decline; anticipating restoration/maintenance of cognitive performance following nutritional supplementation alone may be misdirected. Nutrition declines in …aging, and even more so in AD. While optimization of nutrition should ideally be initiated well before any cognitive decline, we present evidence that the systemic benefit alone of nutritional supplementation at the very minimum warrants initiation along with pharmacological intervention. Show more

Keywords: Alzheimer's disease, cognition, dementia, nutrition, pharmacology, supplement, vitamin

DOI: 10.3233/JAD-2012-112231

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 27-33, 2012

Authors: Sharpe, Laura J. | Wong, Jenny | Garner, Brett | Halliday, Glenda M. | Brown, Andrew J.

Article Type: Short Communication

Abstract: Selective Alzheimer's Disease Indicator-1 (Seladin-1) was originally identified by its down-regulation in the brains of Alzheimer's disease (AD) patients. Here, we re-examine existing data and present new gene expression data that refutes its role as a selective AD indicator. Furthermore, we caution against the use of the name “Seladin-1” and instead recommend adoption of the approved nomenclature, 3β-hydroxysterol Δ24 -reductase (or DHCR24), which describes its catalytic function in cholesterol synthesis. Further work is required to determine what link, if any, exists between DHCR24 and AD.

Keywords: Alzheimer's disease, brain, cholesterol, DHCR24, neuroprotective, Seladin-1

DOI: 10.3233/JAD-2012-111955

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 35-39, 2012

Authors: Alasia, Silvia | Aimar, Patrizia | Merighi, Adalberto | Lossi, Laura

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the major cause of dementia in old people. AD pathology is characterized by amyloid-β (Aβ) deposits in several regions of the brain, and links have been hypothesized between Aβ toxicity and apoptosis. Cerebellar granule cells (CGCs) have been widely used as in vitro tools for molecular studies correlating apoptosis with AD, although the cerebellum is a relatively spared area of the brain in vivo. We have used mixed neuronal-glial cerebellar cultures (NGCCs) and organotypic cerebellar cultures (OCCs) obtained from postnatal mice to assess the toxic effect of the Aβ oligomer 1-40 (Aβ1-40 ) after propidium iodide …uptake in vitro. Our results demonstrate that NGCCs, which are primarily composed of CGCs, are resistant to Aβ1-40 challenge (5–10 μM) when cultured in physiological (5 mM) extracellular KCl ([K+ ]e ) concentrations, i.e., in a condition in which CGCs undergo full maturation. Conversely, when 10 μM Aβ1-40 is given to NGCCs cultured in elevated (25 mM) [K+ ]e (and thus maintained in an immature state), there is a statistically significant increase in cell death. Cell death is by apoptosis, as demonstrated by ultrastructural examination. OCCs are resistant to Aβ challenge in any of the conditions tested (variation of [K+ ]e , presence or absence of serum, or addition of the neprilysin blocker phosphoramidon). Altogether these observations lead us to conclude that cerebellar cells in an organotypic context may be less susceptible to damage by Aβ, raising the question whether isolated CGCs are a reliable assay in drug discovery studies of AD. Show more

Keywords: Alzheimer's disease, amyloid, apoptosis, cerebellum, in vitro studies, organotypic cultures

DOI: 10.3233/JAD-2012-120043

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 41-51, 2012

Authors: Hughes, Timothy M. | Kuller, Lewis H. | Lopez, Oscar L. | Becker, James T. | Evans, Rhobert W. | Sutton-Tyrrell, Kim | Rosano, Caterina

Article Type: Research Article

Abstract: Cholesterol metabolism is believed to play a role in the development of Alzheimer's disease (AD). Oxysterol metabolites of cholesterol, 24S-hydroxycholesterol (24-OHC, a brain-derived oxysterol) and 27-hydroxycholesterol (27-OHC, a peripherally derived oxysterol) cross the blood brain barrier and have been associated with AD. We investigated whether oxysterols were associated with markers of cerebrovascular disease prior to the onset of cognitive impairment. Oxysterols were quantified in 105 participants (average age: 80 ± 4 years) from the Pittsburgh Cardiovascular Health Study Cognition Study who remained cognitively normal at blood draw in 2002, had MRI in 1992 and 1998, and annual cognitive assessment for …incident AD and mild cognitive impairment made by consensus conference between 1998 and 2010. Higher plasma levels of 24-OHC were associated with age, gender, the presence of high grade white matter hyperintensities, and brain infarcts on prior MRI. Participants with higher plasma 24-OHC and a greater ratio of 24-OHC/27-OHC were also more likely to develop incident cognitive impairment over 8 years of follow-up. Higher levels of 24-OHC suggest increased cholesterol metabolism occurring in the brains of participants with cerebrovascular disease prior to the onset of cognitive impairment. Measurement of oxysterols may provide information about cholesterol metabolism and brain disease over the cognitive impairment process. Show more

Keywords: 24S-hydroxycholesterol, cerebrovascular disease, dementia and Alzheimer's disease, oxysterols

DOI: 10.3233/JAD-2012-111460

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 53-61, 2012

Authors: Fawver, Janelle N. | Schall, Hayley E. | Petrofes Chapa, Rachel D. | Zhu, Xiongwei | Murray, Ian V.J.

Article Type: Research Article

Abstract: Glycation is the reaction of a reducing sugar with proteins and lipids, resulting in myriads of glycation products, protein modifications, cross-linking, and oxidative stress. Glycation reactions are also elevated during metabolic dysfunction such as in Alzheimer's disease (AD) and Down's syndrome. These reactions increase the misfolding of the proteins such as tau and amyloid-β (Aβ), and colocalize with amyloid plaques in AD. Thus, glycation links metabolic dysfunction and AD and may have a causal role in AD. We have characterized the reaction of Aβ with reactive metabolites that are elevated during metabolic dysfunction. One metabolite, glyceraldehyde-3-phosphate, is a normal product …of glycolysis, while the others are associated with pathology. Our data demonstrates that lipid oxidation products malondialdehyde, hydroxynonenal, and glycation metabolites (methylglyoxal, glyceraldehyde, and glyceraldehyde-3-phosphate) modify Aβ42 and increase misfolding. Using mass spectrometry, modifications primarily occurred at the amino terminus. However, the metabolite methylglyoxal modified Arg5 in the Aβ sequence. 4-Hydroxy-2-nonenal modifications were similar to our previous publication. To place such modifications into an in vivo context, we stained AD brain tissue for endproducts of glycation, or advanced glycation endproducts (AGE). Similar to previous findings, AGE colocalized with amyloid plaques. In summary, we demonstrate the glycation of Aβ and plaques by metabolic compounds. Thus, glycation potentially links metabolic dysfunction and Aβ misfolding in AD, and may contribute to the AD pathogenesis. This association can further be expanded to raise the tantalizing concept that such Aβ modification and misfolding can function as a sensor of metabolic dysfunction. Show more

Keywords: Advanced glycation endproducts, glyceraldehyde, glyceraldehyde-3-phosphate, glycation, metabolic dysfunction, protein misfolding

DOI: 10.3233/JAD-2012-112114

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 63-73, 2012

Authors: Geerlings, Mirjam I. | Brickman, Adam M. | Schupf, Nicole | Devanand, Davangere P. | Luchsinger, José A. | Mayeux, Richard | Small, Scott A.

Article Type: Research Article

Abstract: We examined whether late-life depression, including depressive symptoms and antidepressant use, was associated with smaller total brain volume, smaller hippocampal volume, and larger white matter hyperintensity (WMH) volume in a large community-based cohort of old persons without dementia. Within the Washington/Hamilton Height-Inwood Columbia Aging Project (WHICAP), a community-based cohort study in northern Manhattan, 630 persons without dementia (mean age 80 years, SD = 5) had volumetric measures of the total brain, hippocampus, and WMH at 1.5 Tesla MRI and data on current depression, defined as a score of 4 or higher on the 10-item Center for Epidemiologic Studies-Depression (CES-D) scale, …or use of antidepressants. Multiple linear regression analyses adjusted for age, gender, ethnicity, education, cardiovascular disease history, and MRI parameters showed that subjects with current depression had smaller relative total brain volume (B = −0.86%; 95% CI −1.68 to −0.05%; p < 0.05), smaller relative hippocampal volume (B = −0.07 ml; 95% CI −0.14 to 0.00 ml; p = 0.05), and larger relative WMH volume (natural logtransformed B = 0.19 ml; 95% CI 0.02 to 0.35 ml; p < 0.05). When examined separately, antidepressant use was significantly associated with smaller total brain, smaller hippocampal, and larger WMH volume, while high CES-D scores were not significantly associated with any of the brain measures, although the direction of association was similar as for antidepressant use. With the caveat that analyses were cross-sectional and we had no formal diagnosis of depression, our findings suggest that in this community-based sample of old persons without dementia, late-life depression is associated with more brain atrophy and more white matter lesions, which was mainly driven by antidepressant use. Show more

Keywords: Antidepressants, brain, cohort, depressive symptoms, elderly, hippocampus, MRI, population-based, white matter hyperintensity

DOI: 10.3233/JAD-2012-112009

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 75-82, 2012

Authors: Taipa, Ricardo | Tuna, Assunção | Damásio, Joana | Pinto, Pedro S. | Cavaco, Sara | Pereira, Sonia | Milterberger-Miltenyi, Gabriel | Galimberti, Daniela | Melo-Pires, Manuel

Article Type: Research Article

Abstract: Frontotemporal lobar degeneration (FTLD) refers to a clinically, pathologically, and genetically heterogeneous group of dementias that arises from the degeneration of the frontal and temporal lobes. Mutations in the progranulin gene (GRN) are a major cause of FTLD with TDP-43 inclusions. Herein, we describe the clinical, neuropathological, and genetic findings in a case of autosomal dominant behavioral variant of frontotemporal dementia (bvFTD) with asymmetrical parkinsonism and prominent visuospatial deficits that carries a novel GRN mutation. This case highlights important clinical characteristics that seem to be common in FTLD GRN-associated patients, such as asymmetrical parkinsonism and parietal symptoms, and that are …correlated to the pathological involvement of striatum (rather than substantia nigra in our case) and parietal lobe. We also emphasize that plasma progranulin level can be useful to infer about the pathogenicity of new GRN mutations. Show more

Keywords: Frontotemporal lobar degeneration (FTLD), parkinsonism, parietal lobe, progranulin, TDP43

DOI: 10.3233/JAD-2012-112084

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 83-90, 2012

Authors: Mouiha, Abderazzak | Duchesne, Simon | the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Biomarkers, both biological and imaging, are indicators of specific changes that characterize Alzheimer's disease (AD) progression in vivo. Knowing the precise relationship between biomarkers and disease severity would allow for accurate disease staging and possible forecasting of decline. Jack et al. suggested as an initial hypothesis that this relationship be sigmoidal; the objective of this article is to determine, using large-scale population data from ADNI, the precise shape of this association. We considered six different models (linear; quadratic; robust quadratic; local quadratic regression; penalized B-spline; and sigmoid) and used the Akaike Information Criterion to gauge how well these models compare …in conforming to the data. We included 576 subjects (229 controls, 193 AD, and 154 mild cognitive impairment subjects who converted to AD) from the ADNI study, for whom baseline data on cerebrospinal fluid amyloid-β (Aβ)42 , phosphorylated tau (p-tau), and total-tau (t-tau), hippocampal volumes, and FDG-PET were available. Analysis of this cross-sectional dataset showed that a local quadratic regression model was 42% more likely than a sigmoid to be the best model for Aβ42 . This ratio augments to 22% and 73% for Penalized B-Spline in the case of p-tau and t-tau, respectively; to 3500% for the linear model for FDG-PET; and to 6700% for the Penalized B-Spline for hippocampal volumes. Preliminary, cross-sectional evidence therefore indicates that the shape of the association with disease severity is non-linear and differs between biomarkers. Show more

Keywords: Akaike information criterion, Alzheimer's disease, biomarkers, dynamic model, statistical analysis

DOI: 10.3233/JAD-2012-111367

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 91-100, 2012