Journal of Alzheimer's Disease - Volume 32, issue 4

Authors: Froestl, Wolfgang | Muhs, Andreas | Pfeifer, Andrea

Article Type: Review Article

Abstract: Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 18 categories according to their mechanism(s) of action, …in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease-modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years. Show more

Keywords: Alzheimer's disease, cognitive enhancers, memantine, memory, nootropics, receptors

DOI: 10.3233/JAD-2012-121186

Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 793-887, 2012

Authors: Kasahata, Naoki | Uchihara, Toshiki | Orimo, Satoshi | Nakamura, Ayako | Makita, Yoshihisa

Article Type: Short Communication

Abstract: A 75-year-old man developed l-dopa non-responsive parkinsonism, supranuclear ophthalmoplegia, neck dorsiflexion, and dementia. Atrophy of the midbrain tegmentum on MRI and normal myocardial uptake of MIBG led to the clinical diagnosis of progressive supranuclear palsy (PSP). Autopsy revealed depigmentation of the substantia nigra and locus ceruleus. Alzheimer's disease pathology was advanced with PSP-like neurofibrillary tangles distribution, and Lewy bodies were abundant in limbic lobe, while scarce in lower brainstem nuclei. Tuft-shaped astrocytes were not apparent. Although decreased myocardial uptake of MIBG is a rule in patients harboring Lewy bodies, its normal uptake may be related to their absence in lower …brainstem nuclei. Show more

Keywords: Alzheimer disease, Lewy body, limbic system, MIBG, progressive supranuclear palsy (PSP)

DOI: 10.3233/JAD-2012-120445

Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 889-894, 2012

Authors: Yasuno, Fumihiko | Tanimukai, Satoshi | Sasaki, Megumi | Ikejima, Chiaki | Yamashita, Fumio | Kodama, Chiine | Mizukami, Katsuyoshi | Asada, Takashi

Article Type: Research Article

Abstract: Although nutrients or agents with antioxidant properties were reported to show a preventive effect on cognitive decline in animal studies, epidemiologic data on select antioxidants have shown conflicting results. We investigated whether a combination of antioxidants from supplements is effective for the improvement of cognitive function of elderly. Forty-one subjects from a community dwelling aged 65 years and older took supplements containing n-3 polyunsaturated fatty acids (n-3 PUFA), lycopene, and Ginkgo biloba extracts (GE) daily for 3 years. The data of 622 subjects without supplement intake were used as control. We investigated the changes in cognitive function during a 3-year …follow-up. We also investigated the influence of apolipoprotein E (APOE) genotype on the effect of antioxidants. We found that a combination of antioxidants improved cognitive function of aged persons after 3 years. Our present study also indicated this improvement in cognitive function with supplement intake in both APOE4 non-carrier (E4−) and APOE4 carrier (E4+) groups. Especially, in E4+, we found a large effect size of the improvement of cognition. When multiple antioxidants are used in combination, they protect against vulnerability to other agents and synergistically potentiate their antioxidant properties. These synergistically potentiated antioxidant effects of agents contribute to the improvement of cognitive function. Show more

Keywords: Antioxidant, apolipoprotein E4 allele (APOE4), cognitive function, Ginkgo biloba extracts (GE), lycopene, n-3 polyunsaturated fatty acid (n-3 PUFA)

DOI: 10.3233/JAD-2012-121225

Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 895-903, 2012

Authors: Lachno, D. Richard | Emerson, Julie K. | Vanderstichele, Hugo | Gonzales, Celedon | Martényi, Ferenc | Konrad, Robert J. | Talbot, Jayne A. | Lowe, Stephen L. | Oefinger, Paul E. | Dean, Robert A.

Article Type: Research Article

Abstract: The aim of this study was to validate the INNO-BIA plasma amyloid-β (Aβ) forms assay for quantification of Aβ1-40 and Aβ1-42 according to regulatory guidance for bioanalysis and demonstrate its fitness for clinical trial applications. Validation parameters were evaluated by repeated testing of human EDTA-plasma pools. In 6 separate estimates, intra-assay coefficients of variation (CV) for repeated testing of 5 plasma pools were ≤9% and relative error (RE) varied between −35% and +22%. Inter-assay CV (n = 36) ranged from 5% to 17% and RE varied from −17% to +8%. Dilutional linearity was not demonstrated for either analyte …using diluent buffer, but dilution with immuno-depleted plasma by 1.67-fold gave results within 20% of target. Analyte stability was demonstrated in plasma at 2–8°C for up to 6 h. Stability during frozen storage up to 12 months and through 3 freeze-thaw cycles at ≤ −70°C was also demonstrated in 5 of 6 individuals but deteriorated thereafter. Neither semagacestat nor LY2811376 interfered with the assay but solanezumab at 500 mg/L reduced recovery of Aβ1-42 by 53%. Specimens from a Phase I human volunteer study of the β-secretase inhibitor LY2811376 were tested at baseline and at intervals up to 12 h after single oral doses, demonstrating a clear treatment effect. During 1,041 clinical assay runs from semagacestat studies over 10 months, the CV for plasma quality control pools at three levels were ≤15% and RE were <10%. In conclusion, the INNO-BIA plasma assay was successfully validated and qualified for use in clinical research. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, assay validation, biomarker, plasma

DOI: 10.3233/JAD-2012-121075

Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 905-918, 2012

Authors: Lanni, Cristina | Garbin, Giulia | Lisa, Antonella | Biundo, Fabrizio | Ranzenigo, Alberto | Sinforiani, Elena | Cuzzoni, Giovanni | Govoni, Stefano | Ranzani, Guglielmina Nadia | Racchi, Marco

Article Type: Research Article

Abstract: COMT (Catechol-O methyltransferase) gene is one of the key players in synaptic plasticity and in learning and memory mechanisms. A single nucleotide polymorphism (rs4680; G to A) in the COMT coding region causes Val158Met aminoacid substitution in the corresponding protein, with Val allele exhibiting a 3- to 4-fold increase in enzyme activity compared to Met. With the purpose of examining the influence of COMT as a genetic risk factor for cognitive impairment, we analyzed a sample of 248 healthy subjects, 276 patients affected by Alzheimer's disease (AD), and 70 subjects with mild cognitive impairment (MCI), the latter condition possibly representing …a prodrome for dementia. All subjects were analyzed for COMT rs4680 polymorphism and APOE genotype. Our study strengthens data showing that APOE ε4 allele is an independent risk factor for AD and also a risk factor for MCI. Neither COMT alleles nor genotypes proved to be independently associated with the risk of AD or MCI in our sample. However, we found an association between COMT GG genotype (Val/Val) and APOE ε4 carrier status and the risk of AD and MCI. In particular, when GG genotype is included into the multinomial analysis, the risk of AD and MCI due to APOE ε4 allele is increased of about 2-3 fold; moreover, the risk conferred by the combination of G and ε4 alleles is more pronounced in male patients. To our knowledge, this synergistic effect is here shown for the first time on a population sample representative of Caucasian patients. Show more

Keywords: Alzheimer's disease, apolipoprotein E, catechol-O methyltransferase (COMT), mild cognitive impairment, polymorphism, risk factor

DOI: 10.3233/JAD-2012-120358

Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 919-926, 2012

Authors: Kim, Min-Jeong | Lee, Kyoung-Min | Son, Young-Don | Jeon, Hyeon-Ae | Kim, Young-Bo | Cho, Zang-Hee

Article Type: Research Article

Abstract: Cholinergic dysfunction is well known to significantly contribute to the cognitive decline in Alzheimer's disease (AD). However, it has not been clarified whether the cholinergic dysfunction is a primary event or a retrograde event secondary to neuronal loss of the cholinergic targets. Analysis of the in vivo neuronal activity of the basal forebrain in the early stages of AD could yield more information about this issue. In the present study, uptake of [18F]-fluorodeoxyglucose (FDG) in the basal forebrain was measured in 13 patients with mild cognitive impairment (MCI), 20 with early AD, and 14 healthy subjects using high-resolution research tomograph-PET. …The FDG uptake was compared among the groups and correlated with the Mini Mental Status Examination (MMSE) score. The MCI patients showed significantly higher FDG uptake in the basal forebrain than the healthy subjects and the AD patients, and those did not developed dementia after 2 years showed even higher uptake than those developed dementia. The basal forebrain metabolism showed an inverted-U relationship with MMSE score in highly educated subjects, and cross-voxel analysis over the whole brain in MCI patients revealed a significant correlation in uptake between the basal forebrain and the fronto-temporal cortices. These findings indicate that in MCI patients, neuronal activity in the basal forebrain is initially increased over that in normal aging and then decreased only with further cognitive decline. The increase is consistent with a secondary compensation against neurodegeneration at target areas, and may provide brain reserve against functional impairments at incipient stages of dementia. Show more

Keywords: Alzheimer's disease, basal nucleus of meynert, cholinergic fibers, 18F-fluorodeoxyglucose, positron-emission tomography

DOI: 10.3233/JAD-2012-120133

Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 927-938, 2012

Authors: Höglund, Kina | Bogstedt, Anna | Fabre, Susanne | Aziz, Ali | Annas, Peter | Basun, Hans | Minthon, Lennart | Lannfelt, Lars | Blennow, Kaj | Andreasen, Niels

Article Type: Research Article

Abstract: There is an increasing demand for biomarkers in clinical treatment trials to demonstrate target engagement and to support disease modification claims. To be able to detect treatment related effects, a prerequisite is that the levels of the biomarker are stable over time or that the change over time is known. In the present study, the stability of α- and β-cleaved soluble amyloid-β protein precursor (sAβPPα and sAβPPβ), Aβ1-40 together with the phosphorylated form of neurofilament heavy/medium (pNfH/M) in cerebrospinal fluid (CSF) was analyzed in a cohort of 51 patients with Alzheimer's disease. In addition, the stability of Aβ1-40 , …Aβ1-42 , and sAβPPβ in plasma was explored. Plasma and CSF was sampled at baseline and after 6-months follow up, and all patients were on stable treatment with acetylcholinesterase inhibitors. During this 6-month longitudinal follow-up, we saw a small, but consistent and statistically significant increase in CSF levels of sAβPPβ (103% of baseline levels) and a statistically significant decrease in the CSF levels of pNfH/M (91% of baseline levels). The mean level of the CSF biomarkers were very stable between baseline and endpoint, with within-patients coefficients of variation (CVs) of 5.84–17.3%, while the variability was larger for the plasma biomarkers, with CVs of 14.1–42.3%. This stability suggests that these biomarkers may have the potential to detect and monitor biochemical changes induced by disease-modifying drugs. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, longitudinal, plasma, stability

DOI: 10.3233/JAD-2012-120976

Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 939-947, 2012

Authors: Bharadwaj, Prashant R. | Verdile, Giuseppe | Barr, Renae K. | Gupta, Veer | Steele, John W. | Lachenmayer, M. Lenard | Yue, Zhenyu | Ehrlich, Michelle E. | Petsko, Gregory | Ju, Shulin | Ringe, Dagmar | Sankovich, Sonia E. | Caine, Joanne M. | Macreadie, Ian G. | Gandy, Sam | Martins, Ralph N.

Article Type: Research Article

Abstract: Latrepirdine (Dimebon™), an anti-histamine, has shown some benefits in trials of neurodegenerative diseases characterized by accumulation of aggregated or misfolded protein such as Alzheimer's disease (AD) and has been shown to promote the removal of α-synuclein protein aggregates in vivo. An important pathway for removal of aggregated or misfolded proteins is the autophagy-lysosomal pathway, which has been implicated in AD pathogenesis, and enhancing this pathway has been shown to have therapeutic potential in AD and other proteinopathies. Here we use a yeast model, Saccharomyces cerevisiae, to investigate whether latrepirdine can enhance autophagy and reduce levels of amyloid-β (Aβ)42 aggregates. …Latrepirdine was shown to upregulate yeast vacuolar (lysosomal) activity and promote transport of the autophagic marker (Atg8) to the vacuole. Using an in vitro green fluorescent protein (GFP) tagged Aβ yeast expression system, we investigated whether latrepirdine-enhanced autophagy was associated with a reduction in levels of intracellular GFP-Aβ42 . GFP-Aβ42 was localized into punctate patterns compared to the diffuse cytosolic pattern of GFP and the GFP-Aβ42 (19 : 34), which does not aggregate. In the autophagy deficient mutant (Atg8Δ), GFP-Aβ42 showed a more diffuse cytosolic localization, reflecting the inability of this mutant to sequester GFP-Aβ42 . Similar to rapamycin, we observed that latrepirdine significantly reduced GFP-Aβ42 in wild-type compared to the Atg8Δ mutant. Further, latrepirdine treatment attenuated Aβ42 -induced toxicity in wild-type cells but not in the Atg8Δ mutant. Together, our findings provide evidence for a novel mechanism of action for latrepirdine in inducing autophagy and reducing intracellular levels of GFP-Aβ42 . Show more

Keywords: Alzheimer's disease, amyloid-β, autophagy, latrepirdine, yeast model

DOI: 10.3233/JAD-2012-120178

Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 949-967, 2012

Authors: Mattila, Jussi | Soininen, Hilkka | Koikkalainen, Juha | Rueckert, Daniel | Wolz, Robin | Waldemar, Gunhild | Lötjönen, Jyrki | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: In the diagnostic process of Alzheimer's disease (AD), there may be considerable delays between first contact to outpatient services and a final, definitive diagnosis. In Europe the average delay is 20 months. Nevertheless, patient data preceding clinical AD diagnoses often contains early signs of the disease. Several studies have analyzed data of mild cognitive impairment (MCI) subjects, showing that conversion from MCI to AD can be predicted with a classification accuracy of 60–80%. This accuracy may not be high enough for influencing diagnostic decisions. In this work, the prediction problem is approached differently; a target prediction accuracy is defined first …and is then used for identifying MCI patients for whom the required accuracy can be reached. The process uses a novel disease state index method in which patient data are statistically compared to a high number of previously diagnosed cases. It is shown that the disease index values derived from heterogeneous patient data can be used for identifying groups of patients for whom the prediction accuracy reaches the previously set target level. The results also show that 12 months before receiving clinical AD diagnoses, approximately half (51.5%, 95% confidence interval: 48.6–54.2%) of MCI subjects who progressed to AD can be classified with a high accuracy of 87.7%, possibly enough to support earlier diagnostic decisions. Show more

Keywords: Clinical decision support, early Alzheimer's disease, mild cognitive impairment, patient selection

DOI: 10.3233/JAD-2012-120934

Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 969-979, 2012

Authors: Huang, Han-Chang | Xu, Ke | Jiang, Zhao-Feng

Article Type: Research Article

Abstract: The deposition of amyloid-β (Aβ) peptides in senile plaques is one of pathological hallmarks of Alzheimer's disease (AD). Mitochondrial dysfunction is an early event of cell apoptosis. Increasing evidence indicates that Aβ induces neuronal apoptosis through mitochondrial dysfunction. Curcumin, an anti-oxidative component of turmeric (Curcuma longa), has shown anti-tumor, anti-inflammatory, and anti-oxidative properties. In this study, we investigated the protective effects of curcumin against mitochondrial dysfunction induced by Aβ. Based on the assay results of mitochondrial metabolic markers, we found that curcumin protects human neuroblastoma SH-SY5Y cells against the Aβ-induced damage of mitochondrial energy metabolism. Curcumin inhibits Aβ-induced mitochondrial depolarization …of membrane potential (Δψm ) and suppresses mitochondrial apoptosis-related proteins including cytochrome c, caspase-3, and Bax, which are activated by Aβ. Aβ-induced disturbances of redox state are linked to mitochondrial dysfunction. Curcumin normalizes cellular antioxidant enzymes (including SOD and catalase) in both protein expression and activity and decreases oxidative stress level in Aβ-treated cells. Both total GSK-3β expression and phospho-Ser9 GSK-3β (pSer9-GSK-3β) are down-regulated in the cells pre-treated with curcumin. This study demonstrates curcumin-mediated neuroprotection against Aβ-induced mitochondrial metabolic deficiency and abnormal alteration of oxidative stress. Inhibition of GSK-3β is involved in the protection of curcumin against Aβ-induced mitochondrial dysfunction. Show more

Keywords: Alzheimer's disease, amyloid-β, curcumin, glycogen synthase kinase-3β, mitochondrial dysfunction, reactive oxygen species

DOI: 10.3233/JAD-2012-120688

Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 981-996, 2012