Volume 34, Number 3, March 2013

Pages 563-588
Urszula Wojda, Jacek Kuznicki (Handling Associate Editor: Piotr Lewczuk)
Alzheimer’s Disease Modeling: Ups, Downs, and Perspectives for Human Induced Pluripotent Stem Cells
Abstract: Major breakthroughs are required to win the war against the increasing threat of Alzheimer’s disease. Until now, however, despite enormous efforts and funds, effective therapies are lacking, and adequate models for drug validation are still unavailable. In this article, we review the available animal and cellular models of different features of human Alzheimer’s disease and critically evaluate their usefulness for understanding the mechanisms of the disease. The majority of the presently used models are based on the amyloid-β and hyperphosphorylated tau hypothesis, which resembles features of familial Alzheimer’s disease. Unfortunately, these models offer limited help for understanding the pathomechanisms of the early stages of sporadic Alzheimer’s disease. Thus, new models are needed to discover ways to treat or delay the onset of Alzheimer’s disease, and we discuss the prospects for such desperately needed models, including human induced pluripotent stem cells and in silico brain models.

Pages 589-594
Rena Li, Jie Cui, Balaji Jothishankar, Juliet Shen, Ping He, Yong Shen (Handling Associate Editor: Jinglong Wu)
Early Reproductive Experiences in Females Make Differences in Cognitive Function Later in Life
Abstract: Women experience dramatic changes in hormones, mood, and cognition through different periods of their reproductive lives, particularly during pregnancy and giving birth. While limited human studies of early pregnancy and motherhood showed alteration of cognitive function in later life, research conducted on rodents showed a persistent improvement of learning and memory performance in females with history of giving birth (primiparous or multiparous) compared to virgin controls (nulliparous). In this mini review, we will focus on the effect of early motherhood on cognitive function later in life, which would provide insight on how reproductive experiences influence women’s health during aging.

Pages 595-600
Carl R. Merril
Is Sporadic Alzheimer's Disease Associated with Diphtheria Toxin?
Abstract: The two major aspects of Alzheimer's disease (AD) that must be considered in a search for causative agents are its association with aging and its widespread epidemiology. While a number of agents have been identified, additional factors may play a role. An association with diphtheria toxin was suggested by observations that vaccinations may provide protective effects, and the observation that decreased proteins synthesis in cortical regions from AD patients is associated with modification of elongation factor 2, the target of diphtheria toxin. While protection against diphtheria toxin is provided by vaccination, the known decline in the immune system associated with aging would result in a renewed sensitivity to the toxin. An association with diphtheria toxin would be consistent with the observations that the bacteria associated with the toxin, Corynebacterium diphtheria, is often found in the nasopharynx and an early symptom of AD is the loss of smell with a disease progression from the entorhinal cortex to the hippocampus and the neocortical areas. If diphtheria toxin is involved in sporadic AD, booster vaccinations given to elderly individuals might result in a decreased incidence of this disease. As booster DPT vaccinations are already recommended for individuals over 65, cognitive testing at the time of the booster and 5 years later, along with similar cognitive testing in age-matched individuals who decline vaccination, might provide an inexpensive method to investigate whether diphtheria toxin plays a role in AD and the efficacy of DPT booster vaccines for AD.

Pages 601-608
Mary C. Tierney, Joanne Ryan, Marie-Laure Ancelin, Rahim Moineddin, Stephanie Rankin, Christie Yao, Neil J. MacLusky
Lifelong Estrogen Exposure and Memory in Older Postmenopausal Women
Abstract: Menopausal changes in endogenous estrogen have been associated with memory decline. However, because earlier findings regarding the effects of lifelong estrogen exposure on memory have been inconsistent, our purpose was to investigate these effects in older postmenopausal women with a comprehensive battery of memory measures. Participants were 126 nondemented naturally postmenopausal women, not currently using hormone therapy (HT), 60 to 89 years of age, who showed normal to below average verbal memory performance on a screening test. Memory measures included tests of visual, verbal, and working memory. Regression analyses were performed with each memory measure as the outcome and length of reproductive period (time between menarche and menopause) as the predictor, controlling for age, education, parity, duration of breastfeeding, previous HT and oral contraceptive use, as well as body mass index and depression. Longer reproductive period was significantly associated with better delayed visual memory, immediate and delayed verbal memory, and working memory. Previous HT use was also significantly associated with better verbal memory and delayed visual memory. Our findings suggest an enduring protective role of endogenous and exogenous estrogen on memory in older postmenopausal women with normal to below average verbal memory performance on a screening test. They also support our contention that the neuroprotective benefits of a longer reproductive period might only be evident after a longer period of postmenopausal estrogen deprivation, which would help clarify why such an association was not previously found in younger postmenopausal women. Replication is required with a larger sample representing a broader cross-section of the aging female population.

Pages 609-620
Thomas van Groen, Inga Kadish, Susanne Aileen Funke, Dirk Bartnik, Dieter Willbold
Treatment with D3 Removes Amyloid Deposits, Reduces Inflammation, and Improves Cognition in Old AβPP/ PS1 Double Transgenic Mice
Abstract: One of the characteristic pathological hallmarks of Alzheimer’s disease (AD) is neuritic plaques. The sequence of events leading to deposition of amyloid-β (Aβ) peptides in plaques is not clear. Here we investigate the effects of D3, an Aβ oligomer directed D-enantiomeric peptide that was obtained from a mirror image phage display selection against monomeric or small oligomeric forms of Aβ42, on Aβ deposition in aged AβPP/PS1 double transgenic AD-model mice. Using Alzet minipumps, we infused the brains of these AD model mice for 8 weeks with FITC-labeled D3, and examined the subsequent changes in pathology and cognitive deficits. Initial cognitive deficits are similar comparing control and D3-FITC-treated mice, but the treated mice show a significant improvement on the last day of testing. Further, we show that there is a substantial reduction in the amount of amyloid deposits in the animals treated with D3-FITC, compared to the control mice. Finally, the amount of activated microglia and astrocytes surrounding Aβ deposits is dramatically reduced in the D3-FITC-treated mice. Our findings demonstrate that treatments with the high affinity Aβ42 oligomer binding D-enantiomeric peptide D3 significantly decrease Aβ deposits and the associated inflammatory response, and improve cognition even when applied only at late stages and high age. Together, this suggests that the treatment reduces the level of Aβ peptide in the brains of AβPP/PS1 mice, possibly by increasing Aβ outflow from the brain. In conclusion, treatments with this D-peptide have great potential to be successful in AD patients.

Pages 621-635
Je-Seong Won, Jinsu Kim, Balasubramaniam Annamalai, Anandakumar Shunmugavel, Inderjit Singh, Avtar K. Singh
Protective Role of S-Nitrosoglutathione (GSNO) against Cognitive Impairmentin Rat Model of Chronic Cerebral Hypoperfusion
Abstract: Chronic cerebral hypoperfusion (CCH), featuring in most of the Alzheimer’s disease spectrum, plays a detrimental role in brain amyloid-β (Aβ) homeostasis, cerebrovascular morbidity, and cognitive decline; therefore, early management of cerebrovascular pathology is considered to be important for intervention in the impending cognitive decline. S-nitrosoglutathione (GSNO) is an endogenous nitric oxide carrier modulating endothelial function, inflammation, and neurotransmission. Therefore, the effect of GSNO treatment on CCH-associated neurocognitive pathologies was determined in vivo by using rats with permanent bilateral common carotid artery occlusion (BCCAO), a rat model of chronic cerebral hypoperfusion. We observed that rats subjected to permanent BCCAO showed a significant decrease in learning/memory performance and increases in brain levels of Aβ and vascular inflammatory markers. GSNO treatment (50 μg/kg/day for 2 months) significantly improved learning and memory performance of BCCAO rats and reduced the Aβ levels and ICAM-1/VCAM-1 expression in the brain. Further, in in vitro cell culture studies, GSNO treatment also decreased the cytokine-induced proinflammatory responses, such as activations of NFκB and STAT3 and expression of ICAM-1 and VCAM-1 in endothelial cells. In addition, GSNO treatment increased the endothelial and microglial Aβ uptake. Additionally, GSNO treatment inhibited the β-secretase activity in primary rat neuron cell culture, thus reducing secretion of Aβ, suggesting GSNO mediated mechanisms in anti-inflammatory and anti-amyloidogenic activities. Taken together, these data document that systemic GSNO treatment is beneficial for improvement of cognitive decline under the conditions of chronic cerebral hypoperfusion and suggests a potential therapeutic use of GSNO for cerebral hypoperfusion associated mild cognitive impairment in Alzheimer’s disease.

Supplementary Data for Won et al. article (PDF)

Pages 637-647
María Recuero, Victor A. Munive, Isabel Sastre, Jesús Aldudo, Fernando Valdivieso, María J. Bullido
A Free Radical‑Generating System Regulates AβPP Metabolism/Processing: Involvement of the Ubiquitin/Proteasome and Autophagy/Lysosome Pathways
Abstract: Oxidative stress is an early event in the pathogenesis of Alzheimer’s disease (AD). We previously reported that, in SK-N-MC cells, the xanthine/xanthine oxidase (X-XOD) free radical generating system regulates the metabolism/processing of the amyloid-β protein precursor (AβPP). Oxidative stress alters the two main cellular proteolytic machineries, the ubiquitin/proteasome (UPS) and the autophagy/lysosome systems, and recent studies have established connections between the malfunctioning of these and the pathogenesis of AD. The aim of the present work was to examine the involvement of these proteolytic systems in the regulation of AβPP metabolism by X-XOD. The proteasome inhibitor MG132 was found to accelerate the metabolism/processing AβPP promoted by X-XOD because it significantly enhances the secretion of α-secretase-cleaved soluble AβPP and also the levels of both carboxy‑terminal fragments (CTFs) produced by α- and β-secretase. Further, MG132 modulated the intracellular accumulation of holo-AβPP and/or AβPP CTFs. This indicates that the X‑XOD modulation of AβPP metabolism/processing involves the UPS pathway. With respect to the autophagy/lysosome pathway, the AβPP processing and intracellular location patterns induced by X-XOD treatment closely resembled those produced by the lysosome inhibitor ammonium chloride. The present results suggest that the regulation of AβPP metabolism/processing by mild oxidative stress requires UPS activity with a simultaneous reduction in that of the autophagy/lysosome system.

Supplementary Data for Recuero et al. article (PDF)

Pages 649-647
Liang Feng, Mei Sian Chong, Wee Shiong Lim, Tih Shih Lee, Simon L Collinson, Philip Yap, Tze Pin Ng
Metabolic Syndrome and Amnestic Mild Cognitive Impairment: Singapore Longitudinal Ageing Study-2 Findings
Abstract: Metabolic syndrome (MetS) is reported to be associated with cognitive decline and dementia, in particular vascular dementia. However, the evidence linking MetS to Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI), a precursor of AD, is inconsistent and limited. This study examined the association of MetS and its components with aMCI and how APOE-εe4 and younger age influenced this association. Participants with aMCI (n=98) and cognitively normal controls (n=802) were identified from baseline data in a second wave cohort of older subjects aged 55 and over in the Singapore Longitudinal Ageing Study-2 (SLAS-2) in 2009/2010. The associations of MetS and its individual components with aMCI were analyzed using logistic regression controlling for age, gender, education, current smoking, alcohol drink, leisure time activities score, Geriatric Depression Scale score, APOE-ε4, and heart disease or stroke. The analysis was repeated for associations stratified by age and APOE-ε4 status. In multivariate analysis, MetS was associated with an elevated risk of aMCI (OR=1.79; 95% CI 1.15-2.77). Among MetS components, central obesity showed a significant association with aMCI (OR=1.77; 95%CI 1.11-2.82). The association between MetS and aMCI remained significant on repeated analysis among subjects free of heart disease and stroke. This association was particularly stronger among participants with APOE-ε4 allele (OR=3.35; 95% CI, 1.03-10.85) and younger (<65 years) participants with APOE-ε4 (OR=6.57; 95% CI, 1.03-41.74). MetS was found to be associated with aMCI, especially in individuals with APOE-ε4 at younger age in this middle-aged and older cohort.

Pages 659-664
Teresa Moreno-Ramos, Julián Benito-León, Alberto Villarejo-Galende, Félix Bermejo-Pareja
Retinal Nerve Fiber Layer Thinning in Dementia Associated with Parkinson’s Disease, Dementia with Lewy Bodies, and Alzheimer’s Disease
Abstract: Optical coherence tomography is a simple, high-resolution technique to quantify the thickness of retinal nerve fiber layer (RNFL). Previous studies have shown that degenerative changes occur in optic nerve fibers and are manifested as thinning of RNLF in patients with Alzheimer’s disease (AD). However, there are no studies on the thickness of the RNLF in other types of dementia, such as dementia with Lewy bodies and dementia associated with Parkinson’s disease. In this study, patients fulfilling diagnostic for AD (n = 10), dementia with Lewy bodies (n = 10), dementia associated with Parkinson’s disease (n = 10), and cognitively normal age-matched controls (n = 10) underwent optical coherence tomography examinations to measure RNLF thickness. There was a significant decrease in RNLF thickness in each type of dementia compared to the control group (Mann-Whitney test, all p < 0.001). Although patients with dementia with Lewy bodies may have a greater thinning than both patients with AD and dementia associated with Parkinson’s disease, the differences were statistically nonsignificant (Kruskal-Wallis test, p = 0.525). The thickness of the RNLF correlated significantly (p < 0.001) with both the Mini-Mental State Examination and the Mattis Dementia Rating Scale scores in all types of dementia; that is to say, the greater the cognitive deterioration, the greater the reduction of thickness of the RNLF. The findings from this study show that retinal involvement measured by optical coherence tomography may also be present in non-AD dementias.

Pages 665-672
Michaela Defrancesco, Josef Marksteiner, Eberhard Deisenhammer, Georg Kemmler, Tanja Djurdjevic, Michael Schocke
Impact of White Matter Lesions and Cognitive Deficits on Conversion from Mild Cognitive Impairment to Alzheimer’s Disease
Abstract: Mild cognitive impairment (MCI) may represent a prodromal stage of dementia and confers a particularly high annual risk of 10-15% for conversion to Alzheimer’s disease (AD). Recent findings suggest that white matter lesion pathology (WML) can negatively influence conversion from MCI to AD. In this study, we examined the predictive value of neuropsychological test results and WML pathology on conversion of MCI to AD. Retrospective neuropsychological and magnetic resonance imaging data were collected for MCI patients seen at the University Clinic of Innsbruck between 2005 and 2011. WML were visually rated using the Fazekas and Scheltens scales. Of the 60 subjects, 31 converted to AD during a follow-up of 18.3±7.4 months and 29 remained stable. Orientation, MMSE score, word list learning and recall, visual memory, and naming scores were significantly lower in MCI patients converting to AD than in non-converters. Converters had significantly higher Fazekas scores and more WML in periventricular regions. Periventricular WML were negatively associated with psychomotor speed, and subcortical WML were negatively correlated with visual memory at baseline in all MCI patients. Low scores in orientation and verbal delayed recall were predictors of progression from MCI to AD. Periventricular WML correlate with lower cognitive function in patients with MCI. However, deficits in orientation and verbal memory, but not vascular changes, turned out as predictive for conversion from MCI to AD. Consequently, a higher WML burden may represent a serious risk factor but not an early symptom for the imminent conversion to AD.

Pages 673-679
Bob Olsson, Joakim Hertze, Mattias Ohlsson, Katarina Nägga, Kina Höglund, Hans Basun, Peter Annas, Lars Lannfelt, Niels Andreasen, Lennart Minthon, Henrik Zetterberg, Kaj Blennow, Oskar Hansson
Cerebrospinal Fluid Levels of Heart Fatty Acid Binding Protein are Elevated Prodromally in Alzheimer’s Disease and Vascular Dementia
Abstract: Heart fatty acid binding protein (HFABP) is expressed in the brain and is elevated in cerebrospinal fluid (CSF) from patients with several forms of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease with dementia, Lewy body dementia, vascular dementia (VaD), and Creutzfeldt-Jakob disease. However, whether HFABP in CSF is a stable biomarker or if it can help predict conversion from mild cognitive impairment (MCI) to AD or VaD has not been well studied. To address the role of HFABP in neurodegeneration, we analyzed CSF levels of HFABP in 96 AD patients and 65 controls and also in 170 patients with MCI with an average follow up time of 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six month interval in between. HFABP levels in CSF were very stable over the six month period (r=0.93, p<0.001). Furthermore, the CSF levels of HFABP were significantly elevated in AD compared with controls after adjustments for age and gender (p<0.001). They were also elevated in the patients with MCI that subsequently converted to AD or VaD compared with those that remained stable (p<0.001 and p<0.05, respectively). However, ROC curve analysis showed that HFABP had lesser predictive value in determining conversion from MCI to AD and VaD than Aβ42, t-tau, and p-tau. In conclusion, HFABP seems to be a stable CSF biomarker that reflects neuronal cell death in several neurodegenerative disorders, including early stages of AD and VaD.

Pages 681-689
Dina Silva, Manuela Guerreiro, Isabel Santana, Ana Rodrigues, Sandra Cardoso, João Maroco, Alexandre de Mendonça
Prediction of Long-Term (5 Years) Conversion to Dementia using Neuropsychological Tests in a Memory Clinic Setting
Abstract: The use of neuropsychological tests to detect cognitive decline in the initial phases of Alzheimer’s disease (AD) has faced significant limitations, namely the fact that most cohort studies of conversion to dementia had relatively short follow-up periods. The aim of the present study is to assess the predictive value for future conversion to dementia of a comprehensive neuropsychological battery applied to a cohort of non-demented patients followed-up for 5 years. Participants (n=250) were selected from the Cognitive Complaints Cohort (CCC) having cognitive complaints, assessment with a comprehensive neuropsychological battery, and a follow-up period of 5 years (unless patients have converted to dementia earlier). During the follow-up period (2.6±1.8 years for converters and 6.1±2.1 years for non-converters), 162 patients (64.8%) progressed to dementia (mostly AD), and 88 (35.2%) did not. A Linear Discriminant Analysis (LDA) model constituted by Digit Span backward, Semantic Fluency, Logical Memory (immediate recall), and Forgetting Index significantly discriminated converters from non-converters (λ Wilks=0.64; χ2 (4)=81.95; p<0.001; RCanonical=0.60). Logical Memory (immediate recall) was the strongest predictor with a standardized canonical discriminant function coefficient of 0.70. The LDA classificatory model showed good sensitivity, specificity and accuracy values (78.8%, 79.9% and 78.6%, respectively) of the neuropsychological tests to predict long-term conversion to dementia. The present results show that it is possible to predict, on the basis of the initial clinical and neuropsychological evaluation, whether non-demented patients with cognitive complaints will probably convert to dementia, or remain stable, at a reasonably long and clinically relevant term.

Pages 691-700
Jennifer H.K. Choi*, Gurjinder Kaur*, Matthew J. Mazzella, Jose Morales-Corraliza, Efrat Levy, Paul M. Mathews *These authors contributed equally to this work.
Early Endosomal Abnormalities and Cholinergic Neuron Degeneration in Amyloid-β Protein Precursor Transgenic Mice
Abstract: Early endosomal changes, a prominent pathology in neurons early in Alzheimer’s disease, also occur in neurons and peripheral tissues in Down syndrome. While in Down syndrome models, increased amyloid-β protein precursor (AβPP) expression is known to be a necessary contributor on the trisomic background to this early endosomal pathology, increased AβPP alone has yet to be shown to be sufficient to drive early endosomal alterations in neurons. Comparing two AβPP transgenic mouse models, one that contains the AβPP Swedish K670N/M671L double mutation at the β-cleavage site (APP23) and one that has the AβPP London V717I mutation near the γ-cleavage site (APPLd2), we show significantly altered early endosome morphology in fronto-parietal neurons as well as enlargement of early endosomes in basal forebrain cholinergic neurons of the medial septal nucleus in the APP23 model, which has the higher levels of AβPP β-C-terminal fragment (βCTF) accumulation. Early endosomal changes correlate with a marked loss of the cholinergic population, which is consistent with the known dependence of the large projection cholinergic cells on endosome-mediated retrograde neurotrophic transport. Our findings support the idea that increased expression of AβPP and AβPP metabolites in neurons is sufficient to drive early endosomal abnormalities in vivo, and that disruption of the endocytic system is likely to contribute to basal forebrain cholinergic vulnerability.

Pages 701-706
Sid E. O’Bryant, Leigh Johnson, Melissa Edwards, Holly Soares, Michael D. Devous, Sr., Sarah Ross, Geoffrey Rohlfing, James Hall, for the Texas Alzheimer’s Research & Care Consortium
The Link between C-Reactive Protein and Alzheimer’s Disease Among Mexican Americans
Abstract: Background: The aim of this study is to evaluate the link between C-reactive protein (CRP) and Alzheimer’s disease (AD) and mild cognitive impairment (MCI) among Mexican Americans. Methods: Non-fasting serum CRP levels, Mini-Mental State Examination scores, and Clinical Dementia Rating scale (CDR) scores were analyzed from 1,066 participants (Mexican American n=471; non-Hispanic n=595) of the Texas Alzheimer’s Research & Care Consortium. Results: Among the total cohort, CRP levels among AD cases were significantly decreased as compared to normal controls (p<0.001) and MCI cases (p=0.002). CRP levels among MCI cases were decreased relative to controls (p=0.03). Among Mexican American and non-Hispanic AD cases, CRP levels were significantly decreased among AD cases as compared to controls. CRP levels were only associated with disease severity (CDR scores) among non-Hispanics (p=0.03) AD cases. Conclusions: These results show that while CRP levels are decreased among Mexican American AD cases, CRP does not appear to be related to clinical variables as it is among non-Hispanic whites.

Pages 707-725
Claudio Babiloni, Fabrizio Vecchio, Claudio Del Percio, Sara Montagnese, Sami Schiff, Roberta Lizio, Giorgia Chini, Gaetano Serviddio, Nicola Marzano, Andrea Soricelli, Giovanni B. Frisoni, Paolo M. Rossini, Piero Amodio
Resting State Cortical Electroencephalographic Rhythms in Covert Hepatic Encephalopathy and Alzheimer’s Disease
Abstract: Patients suffering from prodromal (i.e., amnestic mild cognitive impairment, aMCI) and overt Alzheimer’s disease (AD) show abnormal cortical sources of resting state electroencephalographic (EEG) rhythms. Here we tested the hypothesis that these sources show extensive abnormalities in liver cirrhosis (LC) patients with a cognitive impairment due to covert and diffuse hepatic encephalopathy (CHE). EEG activity was recorded in 64 LC (including 21 CHE), 21 aMCI, 21 AD, and 21 cognitively intact (Nold) subjects. EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 Hz). EEG cortical sources were estimated by LORETA. Widespread sources of theta (all but frontal), alpha 1 (all but occipital), and alpha 2 (parietal, temporal) rhythms were higher in amplitude in all LC patients than in the Nold subjects. In these LC patients, the activity of central, parietal, and temporal theta sources correlated negatively, and parietal and temporal alpha 2 sources correlated positively with an index of global cognitive status. Finally, widespread theta (all but frontal) and alpha 1 (all but occipital) sources showed higher activity in the sub-group of LC patients with CHE than in the patients with aMCI or AD. These results unveiled the larger spatial-frequency abnormalities of the resting state EEG sources in the CHE compared to the AD condition.

Pages 727-739
Bhumsoo Kim, Carey Backus, SangSu Oh, Eva L. Feldman (Handling Associate Editor: Inhee Mook-Jung)
Hyperglycemia-Induced Tau Cleavage in vitro and in vivo: A Possible Link between Diabetes and Alzheimer’s Disease
Abstract: Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer’s disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. In parallel, AD patients have a higher than normal tendency to develop type 2 diabetes or impaired fasting glucose. Tau is the major component of neurofibrillary tangles, one of the hallmarks of AD pathology. The current study examined the effect of hyperglycemia on tau modification. Glucose treatment of rat embryonic cortical neurons results in concentration-dependent apoptosis and caspase-3 activation. These changes are well correlated with glucose time- and concentration-dependent tau cleavage. Aβ treatment induces tau cleavage and when added together with glucose, there is an additive effect on caspase activation, apoptosis, and tau cleavage. Tau cleavage is partially blocked by the caspase inhibitor, ZVAD. Cleaved tau displays a punctate staining along the neurites and colocalizes with cleaved caspase-3 in the cytoplasm. Both type 1 and type 2 diabetic mice display increased tau phosphorylation in the brain. In agreement with the effects of glucose on tau modifications in vitro, there is increased tau cleavage in the brains of ob/ob mice; however, tau cleavage is not observed in type 1 diabetic mouse brains. Our study demonstrates that hyperglycemia is one of major factors that induce tau modification in both in vitro and in vivo models of diabetes. We speculate that tau cleavage in diabetic conditions (especially in type 2 diabetes) may be a key link for the increased incidence of AD in diabetic patients.

Pages 741-754
Janusch Blautzik, Daniel Keeser, Albert Berman, Marco Paolini, Valerie Kirsch, Sophia Mueller, Ute Coates, Maximilian Reiser, Stefan J. Teipel, Thomas Meindl
Long-Term Test-Retest Reliability of Resting-State Networks in Healthy Elderly Subjects and Mild Cognitive Impairment Patients
Abstract: The investigation of cerebral resting-state networks (RSNs) by functional magnetic resonance imaging (fMRI) is a promising tool for the early diagnosis and follow-up of neuropsychiatric and neurodegenerative disorders like Alzheimer’s disease (AD). In this context, the determination of inter-session reliability of these networks is crucial. However, data on network reliability in healthy elderly subjects is rare and does not exist for patients with amnestic mild cognitive impairment (aMCI), a prodromal stage of AD. Therefore, the aim of this study was to investigate the long-term test-retest reliability of RSNs in both groups. Twelve healthy controls (HC) and 13 aMCI patients underwent resting-state fMRI and neuropsychological testing (CERAD test battery) twice, at baseline and after 13-16 months. Resting-state fMRI data was decomposed into independent components using independent component analysis. Inter-session test-retest reliability of the resulting RSNs was determined by calculating voxel-wise intra-class correlation coefficients. Overall test-retest reliability of corresponding RSNs was moderate to high in both groups, but significantly higher in the HC group compared to the aMCI group (p<0.001), while the cognitive performance within the CERAD test battery remained stable over time in either group. Most reliable RSNs derived from the HC group and were associated with sensory and motor as well as higher order cognitive and the default-mode function. Particularly low reliability was found in basal frontal regions, which are known to be prone to susceptibility-induced noise. We conclude that stable RSNs may represent healthy aging, whereas decreased RSN reliability may indicate progressive neuro-functional alterations before the actual manifestation of clinical symptoms.

Pages 755-767
Xian-Hui Li, Xin Xin, Yan Wang, Jian-zhao Wu, Zhen-dong Jin, Li-na Ma, Chun-jie Nie, Xiao Xiao, Yan Hu, Man-wen Jin
Pentamethylquercetin Protects Against Diabetes-Related Cognitive Deficits in Diabetic Goto-Kakizaki Rats
Abstract: Diabetic patients have a significantly higher risk of developing all forms of dementia. Pentamethylquercetin (PMQ) has been proven to have potential as an anti-diabetic agent. Nevertheless, whether PMQ can improve diabetes-induced cognitive dysfunction has not been investigated. To address this, we evaluated the effectiveness and underlying mechanisms of PMQ for ameliorating diabetes-related cognitive dysfunction in vivo and in vitro. Our results showed that Goto-Kakizaki (GK) rats displayed impairment in their learning abilities and memory capabilities. Furthermore, GK rats reflected cognitive dysfunction in proportion to the intensity of insulin resistance index. In addition, dendritic spine density and the % cell viability significantly decreased in hippocampus neurons. High glucose conditions induced hippocampal neurons damage, inflicted dendritic spine dysontogenesis, and reduced Akt/cAMP response element-binding protein activation. Treatment with PMQ in GK rats significantly ameliorated cognitive deficits and neuronal damage and increased dendritic spine density, at least in part, by improving insulin resistance and metabolic disorders. Furthermore, PMQ significantly activated the Akt/cAMP response element-binding protein pathway and increased the expression of memory-related proteins in the downstream part of the Akt/cAMP response element-binding protein pathway, such as synaptophysin and glutamate receptor 1. In addition, PMQ inhibited high glucose-induced cellular toxicity. LY294002 appeared to partly inhibit PMQ-mediated protective effects in hippocampal neurons. The results suggest that insulin resistance could predominantly reduce Akt/cAMP response element-binding protein activation in the brain, which is associated with a higher risk of cognitive dysfunction. PMQ could provide a new potential option for the prevention of cognitive dysfunction in diabetes.

Pages 769-780
Ana Espinosa, Montserrat Alegret , Sergi Valero, Georgina Vinyes-Junqué, Isabel Hernández, Ana Mauleón, Maitée Rosende-Roca, Agustín Ruiz, Oscar López, Lluís Tárraga, Mercè Boada
A Longitudinal Follow-Up of 550 Mild Cognitive Impairment Patients: Evidence for Large Conversion to Dementia Rates and Detection of Major Risk Factors Involved
Abstract: The most recent studies about mild cognitive impairment (MCI) are focused on the search for factors that make patients more vulnerable to conversion to dementia, mainly Alzheimer’s disease (AD). The aim of this study was to determine which neuropsychological test performances, including episodic memory profiles, and genetic risk factors (APOE ε4) better predict early conversion to dementia among the four MCI subtypes. Data from 550 MCI patients were analyzed for the purpose of this study and were classified according to Petersen’s criteria (2004), and also taking into account the absence (probable MCI) or presence (possible MCI) of comorbidities that could explain cognitive deficits. MCI cases were divided into Probable amnestic (Pr-aMCI) (n=115), probable non-amnestic (Pr-naMCI) (n=37), possible amnestic (Pss-aMCI) (n=234), and possible non-amnestic (Pss-naMCI) (n=164), single or multiple domain. In the whole MCI sample, regression analysis showed that low performances on Orientation, Verbal Delayed Recall of the Word List Learning test from WMS-III, and Luria’s Clock test were associated with conversion to dementia, independently of APOE ε4 allele. Cox proportional-hazards showed that the Probable MCI subtype, presence of storage memory impairment, multiple domain condition, and presence of at least one ε4 allele increased the risk of conversion to dementia. Multivariate survival and Kapplan-Meier analyses showed that the Pr-aMCI with storage memory impairment had the most and closest risk of conversion to dementia. In conclusion, the Pr-aMCI subset of patients had 8.5 times more risk of converting to dementia than the Pss-naMCI group, who displayed the slowest conversion rate to dementia.

Supplementary Data for Espinosa et al. article (PDF)

Pages 781-793
Gillian A. Scullion, Katherine N. Hewitt, Marie-Christine Pardon (Handling Associate Editor: Laura Petrosini)
Corticotropin-Releasing Factor Receptor 1 Activation During Exposure to Novelty Stress Protects Against Alzheimer’s Disease-Like Cognitive Decline in AβPP/PS1 Mice
Abstract: A lifestyle rich in physical and mental activities protects against Alzheimer’s disease (AD) but the underlying mechanisms are unclear. We have proposed that this is mediated by a stress response and have shown that repeated exposure to novelty stress, which induces physical and exploratory activities, delays the progression of AD-like pathology in the TASTPM mouse model. Here, we aimed to establish the role played by corticotrophin-releasing factor receptor 1 (CRFR1), a major component of the stress axis, in TASTPM’s behavioral and neuroendocrine responses to novelty and related protective effects. We show that the stress response of TASTPM mice is altered with reduced CRFR1-mediated neuroendocrine and behavioral responses to novelty and a distinct profile of behavioral responses. Repeated novelty-induced CRFR1 activation, however, mediated the improved contextual fear memory and extinction performance of TASTPM mice and increased hippocampal and fronto-cortical levels of synaptophysin, a marker of synaptic density, and fronto-cortical levels of the post-synaptic marker PSD95. The N-methyl-D-aspartate receptor (NMDAR) is the major receptor for synaptic plasticity underlying learning and memory. Although novelty-induced NMDAR activation contributed to enhancement of fear memory and synaptophysin levels, antagonism of CRFR1 and NMDAR prevented the novelty-induced increase in hippocampal synaptophysin levels but reversed the other effects of CRFR1 inactivation, i.e., the enhancement of contextual fear extinction and fronto-cortical synaptophysin and PSD95 levels. These findings suggest a novel mechanism whereby a stimulating environment can delay AD symptoms through CRFR1 activation, facilitating NMDAR-mediated synaptic plasticity and synaptogenesis in a region-dependent manner, either directly, or indirectly, by modulating PSD95.

Supplementary Data for Scullion et al. article (PDF)