Journal of Alzheimer's Disease - Volume 42, issue 4

Authors: Holler, Christopher J. | Davis, Paulina R. | Beckett, Tina L. | Platt, Thomas L. | Webb, Robin L. | Head, Elizabeth | Murphy, M. Paul

Article Type: Research Article

Abstract: Recent genome wide association studies have implicated bridging integrator 1 (BIN1) as a late-onset Alzheimer's disease (AD) susceptibility gene. There are at least 15 different known isoforms of BIN1, with many being expressed in the brain including the longest isoform (iso1), which is brain-specific and localizes to axon initial segments and nodes of Ranvier. It is currently unknown what role BIN1 plays in AD. We analyzed BIN1 protein expression from a large number (n = 71) of AD cases and controls from five different brain regions (hippocampus, inferior parietal cortex, inferior temporal cortex, frontal cortex (BA9), and superior and middle …temporal gyri). We found that the amount of the largest isoform of BIN1 was significantly reduced in the AD brain compared to age-matched controls, and smaller BIN1 isoforms were significantly increased. Further, BIN1 was significantly correlated with the amount of neurofibrillary tangle (NFT) pathology but not with either diffuse or neuritic plaques, or with the amount of amyloid-β peptide. BIN1 is known to be abnormally expressed in another human disease, myotonic dystrophy, which also features prominent NFT pathology. These data suggest that BIN1 is likely involved in AD as a modulator of NFT pathology, and that this role may extend to other human diseases that feature tau pathology. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, cellular nucleic acid binding protein, myotonic dystrophy, tau, ZNF9

DOI: 10.3233/JAD-132450

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1221-1227, 2014

Authors: Rodriguez-Ortiz, Carlos J. | Baglietto-Vargas, David | Martinez-Coria, Hilda | LaFerla, Frank M. | Kitazawa, Masashi

Article Type: Research Article

Abstract: MicroRNAs are a group of small RNAs that regulate diverse cellular processes including neuronal function. Recent studies have shown that dysregulation of specific microRNAs is critically involved in the development of Alzheimer's disease (AD). Most of these reports have focused on microRNAs implicated in alterations of amyloid-β and tau. However, studies exploring the relation between microRNAs dysregulation in AD and synaptic plasticity are scarce despite the well-known involvement of microRNAs in synaptic plasticity. Since impairments in synaptic plasticity and neuronal loss are two important features displayed in AD patients, it is feasible to hypothesize that alterations in plasticity-related microRNAs underlie …AD progression. Here, levels of a small number of microRNAs implicated in normal neuronal function and/or plasticity were examined in an AD model. Twelve-month old 3xTg-AD mice with plaques and tangles presented a significant upregulation of miR-181 in the hippocampus compared to age-matched wild type mice. Increased miR-181 was not detected in pre-pathological 3xTg-AD mice. Analysis of predicted targets of miR-181 identified c-Fos and SIRT-1, proteins critically involved in memory formation. Both c-Fos and SIRT-1 levels were significantly decreased in the ventral hippocampus of twelve-month old 3xTg-AD mice. Overexpression of miR-181 in SH-SY5Y cells significantly decreased c-Fos and SIRT-1, strongly suggesting that miR-181 directly regulates the expression of these two proteins. These findings indicate a connection between miR-181 and proteins involve in synaptic plasticity and memory processing in a transgenic mouse model of AD. Our results suggest that microRNAs involved in synaptic plasticity might be an important factor that contributes to AD neuropathology. Show more

Keywords: Alzheimer's disease, miRNA, sirtuin-1, synaptic plasticity, translational regulation

DOI: 10.3233/JAD-140204

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1229-1238, 2014

Authors: Van der Mussele, Stefan | Fransen, Erik | Struyfs, Hanne | Luyckx, Jill | Mariën, Peter | Saerens, Jos | Somers, Nore | Goeman, Johan | De Deyn, Peter P. | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Behavioral and psychological signs and symptoms of dementia (BPSD) belong to the core symptoms of dementia and are also common in mild cognitive impairment (MCI). Objective: This study would like to contribute to the understanding of the prognostic role of BPSD in MCI for the progression to dementia due to Alzheimer’s disease (AD). Methods: Data were generated through an ongoing prospective longitudinal study on BPSD. Assessment was performed by means of the Middelheim Frontality Score, Behave-AD, Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia (CSDD), and Geriatric Depression Scale 30-questions (GDS-30). Cox proportional hazard …models were used to test the hypothesis that certain BPSD in MCI are predictors of developing AD. Results: The study population consisted of 183 MCI patients at baseline. At follow-up, 74 patients were stable and 109 patients progressed to AD. The presence of significant depressive symptoms in MCI as measured by the CSDD (HR: 2.06; 95% CI: 1.23–3.44; p = 0.011) and the GDS-30 (HR: 1.77; 95% CI: 1.10–2.85; p = 0.025) were associated with progression to AD. The severity of depressive symptoms as measured by the GDS-30 was a predictor for progression too (HR: 1.06; 95% CI: 1.01–1.11; p = 0.020). Furthermore, the severity of agitated behavior, especially verbal agitation and the presence of purposeless activity, was also associated with progression, whereas diurnal rhythm disturbances were associated with no progression to AD. Conclusion: Depressive symptoms in MCI appear to be predictors for progression to AD. Show more

Keywords: Alzheimer's disease, association, BPSD, Cox proportional hazard, dementia, depression, depressive symptoms, mild cognitive impairment, predictor, prognostic value

DOI: 10.3233/JAD-140405

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1239-1250, 2014

Authors: Ford, Andrew H. | Almeida, Osvaldo P. | Flicker, Leon | Garrido, Griselda J. | Greenop, Kathryn R. | Foster, Jonathan K. | Etherton-Beer, Christopher | van Bockxmeer, Frank M. | Lautenschlager, Nicola T.

Article Type: Research Article

Abstract: Reduced awareness of cognitive deficits in mild cognitive impairment (MCI) is associated with poorer outcomes although little is known about the anatomical correlates of this. We examined the association of insight and grey matter volume using a voxel-based morphometry approach in 65 volunteers with MCI and 55 healthy age-matched controls. Participants with MCI had multiple areas of subtle grey matter volume loss compared with controls, although these did not survive correction for multiple comparisons. These were predominantly in the temporal and anterior portions of the brain. Individuals with MCI did not differ from each other on a number of demographic …and cognitive variables according to level of insight. Reduced awareness of cognitive deficits was associated with few differences in grey matter volume apart from a subtle loss of grey matter in the medial frontal gyri. Given the modest nature of these findings, the routine assessment of insight in non-clinical populations of individuals with MCI is therefore not supported. Prospective data in larger samples, however, would be helpful to clarify this further and determine if impaired insight predicts brain atrophy and cognitive decline. Show more

Keywords: Awareness, grey matter, insight, mild cognitive impairment

DOI: 10.3233/JAD-132678

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1251-1259, 2014

Authors: Galimberti, Daniela | Villa, Chiara | Fenoglio, Chiara | Serpente, Maria | Ghezzi, Laura | Cioffi, Sara M.G. | Arighi, Andrea | Fumagalli, Giorgio | Scarpini, Elio

Article Type: Research Article

Abstract: Several micro(mi)RNA are deregulated in brain, cerebrospinal fluid (CSF), and serum/plasma from patients with Alzheimer's disease (AD). The aim of the study was to profile circulating miRNAs in serum as non-invasive biomarkers for AD, correlating them with those identified in CSF, the biological fluid which better reflects biochemical changes occurring during pathological processes in the brain and may provide a robust indicator of AD-related disease pathogenesis thanks to the evidence of low amyloid and high levels of tau and hyperphosphorylated tau. Using a two-step analysis (array and validation through real-time PCR), a down-regulation (mean fold change ± SEM) of miR-125b …(0.415 ± 0.11 versus 1.381 ± 0.36, p = 0.009), miR-23a (0.111 ± 0.03 versus 0.732 ± 0.14, p < 0.001), and miR-26b (0.414 ± 0.11 versus 1.353 ± 0.39, p < 0.01), out of 84 tested, was shown in serum from 22 AD patients compared with 18 non-inflammatory and 8 inflammatory neurological controls (NINDCs and INDCs) and 10 patients with frontotemporal dementia. Significant down-regulation of miR-125b and miR-26b was also confirmed in CSF from AD patients versus NINDCs (miR-125b: 0.089 ± 0.03 versus 0.230 ± 0.08, p < 0.001; miR-26b: 0.217 ± 0.06 versus 1.255 ± 0.29, p < 0.001, mean fold change ± SEM, respectively), whereas data were not replicated for miR-23a. In serum, miR-125b had an AUC of 0.82 to distinguish AD from NINDCs (95% CI: 0.65–0.98, p = 0.005). In conclusion, we demonstrated that cell-free miR-125b serum levels are decreased in serum from patients with AD as compared with NINDC and distinguish between AD and NINDCs with an accuracy of 82%. Show more

Keywords: Alzheimer's disease, biomarker, miRNA, serum

DOI: 10.3233/JAD-140756

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1261-1267, 2014

Authors: Winkler, Angela | Dlugaj, Martha | Weimar, Christian | Jöckel, Karl-Heinz | Erbel, Raimund | Dragano, Nico | Moebus, Susanne | on behalf of the Heinz Nixdorf Recall Study Investigative Group

Article Type: Research Article

Abstract: Background: Several studies reported on the association of type 2 diabetes (T2DM) with dementia. Studies on the association of T2DM and mild cognitive impairment (MCI) are rare. Objective: To evaluate the gender-specific association of T2DM with MCI and MCI subtypes (amnestic MCI (aMCI) and non-amnestic MCI (naMCI)) in a middle-aged (50–65 years) and old-aged (66–80 years) population-based study sample. Methods: We compared 560 participants with MCI (aMCI n = 289, naMCI n = 271) with 1,376 cognitively normal participants from the Heinz Nixdorf Recall study. Diabetic status was based on self-reported physician’s diagnosis or treatment with …anti-diabetic medication. We performed group comparisons regarding all cognitive subtests for participants with and without T2DM. Logistic regression models (adjusted for age, education, cardiovascular risk factors, and depression) were used to determine the association of T2DM with MCI and MCI subtypes. Results: In the middle-aged group, fully adjusted models showed an association (odds ratio, 95% CI) of T2DM with MCI that was more pronounced in men (total: 2.03, 1.23–3.36, men: 2.16, 1.12–4.14, women 1.69, 0.73–3.89). T2DM was associated with MCI subtypes (aMCI: 2.01, 1.08–3.73; naMCI: 2.06, 1.06–3.98), whereas, the association was stronger with naMCI in men (2.61, 1.14–5.98) and with aMCI in women (3.02, 1.27–7.17). We found no total or gender-specific association of T2DM with MCI or MCI subtypes in the old-aged group. Conclusions: Our data show that T2DM is associated with MCI and MCI subtypes in middle-aged, but not in old-aged participants. Furthermore, the results indicate a gender-specific vulnerability of T2DM on cognition, especially in MCI subtypes. Show more

Keywords: Aging, gender, mild cognitive impairment, population-based studies, type 2 diabetes mellitus

DOI: 10.3233/JAD-140696

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1269-1277, 2014

Authors: Chirila, Florin V. | Khan, Tapan K. | Alkon, Daniel L.

Article Type: Research Article

Abstract: The inaccuracy of the diagnosis for Alzheimer's disease (AD) has made its therapeutic intervention difficult, particularly early enough to prevent significant neurodegeneration and cognitive dysfunction. Here, we describe a novel, highly accurate peripheral diagnostic for AD patients based on quantitatively measured aggregation rate of human skin fibroblasts. The elevated aggregation rate with increasing cell density in AD cases is the basis of this new biomarker. The new biomarker was successfully cross-validated with two more mature assays, AD-Index, based on the imbalances of ERK1/2, and Morphology, based on network dynamics, and showed 92% overlap. A significant number of cases tested with …this new biomarker were freshly obtained (n = 29), and 82% of the cases are hyper-validated cases, i.e., autopsy and/or genetically confirmed AD or non-Alzheimer's disease demented patients (Non-ADD) and non-demented age-matched controls. Furthermore, we show that by using a simple majority rule, i.e., two out of the three assays have the same outcome, we significantly increase the agreement with clinical AD diagnosis (100%). Based on the high accuracy of this strategy, the biomarker profile appears to accurately identify AD patients for therapeutic intervention. Show more

Keywords: Aggregation rate, Alzheimer's disease, cross-validation, majority rule, skin fibroblasts

DOI: 10.3233/JAD-140672

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1279-1294, 2014

Authors: Meng, Xiang-Fei | Yu, Jin-Tai | Wang, Hui-Fu | Tan, Meng-Shan | Wang, Chong | Tan, Chen-Chen | Tan, Lan

Article Type: Research Article

Abstract: Background/Objective: We examine whether midlife vascular risk factors (VRFs) are associated with increased risk of incident Alzheimer’s disease (AD) in a systematic review and meta-analysis of published cohort studies. Methods: Original cohort studies were included if they reported adjusted combined odds ratio (COR) and corresponding 95% confidence intervals (CIs) or enough information to quantify the association between risk for AD in late-life and baseline VRFs of midlife. Results: There were positive and significant associations between high blood pressure (COR 1.31; 95% CI: 1.01–1.70), hypercholesterolemia (COR 1.72; 95% CI: 1.32–2.24), obesity (COR 1.88; 95% CI: 1.32–2.69), and …diabetes mellitus in midlife (COR 1.4; 95% CI: 1.25–1.57). Smoking and hyperhomocysteinemia (although only one high-quality paper) were also associated with an increased risk of AD generally. Conclusions: These results strengthen the epidemiological evidence that VRFs of midlife significantly increase risk for AD. Show more

Keywords: Alzheimer's disease, diabetes mellitus, high blood pressure, hypercholesterolemia, hyperhomocysteinemia, meta-analysis, midlife vascular risk factors, obesity, smoking, systematic review

DOI: 10.3233/JAD-140954

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1295-1310, 2014

Authors: Colucci, Luisa | Bosco, Massimiliano | Fasanaro, Angiola Maria | Gaeta, Giuseppe Lucio | Ricci, Giovanna | Amenta, Francesco

Article Type: Research Article

Abstract: Background/Objective: Alzheimer’s disease (AD) is a very costly pathology. Total costs of AD result from the sum of direct and indirect costs. Intangible costs represent an additional burden that is difficult to quantify. This paper has reviewed the evaluation of the costs of AD and the methodologies to estimate them, and proposes the use of some tools which may be useful in establishing the financial weight of the disease. Method: A systematic literature search was conducted using the Pubmed and Medline databases as a source of published papers. Results: In AD, direct and indirect costs and …their sum (total costs) are very high and tend to increase parallel with the evolution of the pathology. The evolution of AD is characterized by the loss of functional autonomy, the onset of behavioral and sleep disorders, and the development of delusions and hallucinations. This requires more frequent medical examinations and hospitalizations resulting in higher direct costs, which become the relevant weight. None of the papers reviewed investigated intangible cost. Conclusion: The calculation of costs of AD is frequently based on cognitive decline and the degree of dependence of patients. The evaluation of intangible costs (psychological pain of the patient and of the unpaid caregivers’ and their impaired quality of life) is a missing aspect in all reviewed studies. Due to the complexity of AD, it will be necessary to adopt cost evaluation systems including the different dimensions of the problem and its various aspects. Show more

Keywords: Costs of Alzheimer's disease, direct costs, evaluation costs, indirect costs, intangible costs, total costs

DOI: 10.3233/JAD-131556

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1311-1324, 2014

Authors: O'Bryant, Sid E. | Xiao, Guanghua | Zhang, Fan | Edwards, Melissa | German, Dwight C. | Yin, Xiangling | Como, Tori | Reisch, Joan | Huebinger, Ryan M. | Graff-Radford, Neill | Dickson, Dennis | Barber, Robert | Hall, James | O'Suilleabhain, Padraig | Grammas, Paula

Article Type: Research Article

Abstract: Background: There is a significant need for rapid and cost-effective biomarkers of Alzheimer’s disease (AD) for advancement of clinical practice and therapeutic trials. Objective: The aim of the current study was to cross-validate our previously published serum-based algorithm on an independent assay platform as well as validate across tissues and species. Preliminary analyses were conducted to examine the utility in distinguishing AD from non-AD neurological disease (Parkinson’s disease, PD). Methods: Serum proteins from our previously published algorithm were quantified from 150 AD cases and 150 controls on the Meso Scale Discovery (MSD) platform. Serum samples were …analyzed from 49 PD cases and compared to a random sample of 51 AD cases and 62 controls. Support vector machines (SVM) were used to discriminate PD versus AD versus controls. Human and AD mouse model microvessel images were quantified with HAMAMATSU imaging software. Mouse serum biomarkers were assayed via MSD. Results: Analysis of 21 serum proteins from 150 AD cases and 150 controls yielded an algorithm with sensitivity and specificity of 0.90 for correctly classifying AD. This multi-marker approach was then validated across species and tissue. Assay of the top proteins in human and AD mouse model brain microvessels correctly classified 90–100% of the samples. SVM analyses were highly accurate at distinguishing PD versus AD versus controls. Conclusions: This serum-based biomarker panel should be tested in a community-based setting to determine its utility as a first-line screen for AD and non-AD neurological diseases for primary care providers. Show more

Keywords: Alzheimer's disease, blood-based biomarkers, serum, species, tissue

DOI: 10.3233/JAD-141041

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1325-1335, 2014

Authors: García-Casares, Natalia | Jorge, Ricardo E. | García-Arnés, Juan A. | Acion, Laura | Berthier, Marcelo L. | Gonzalez-Alegre, Pedro | Nabrozidis, Alejandro | Gutiérrez, Antonio | Ariza, María José | Rioja, Jose | González-Santos, Pedro

Article Type: Research Article

Abstract: Background/Objective: The aim was to assess the neuropsychological performance of a group of middle-aged patients with well-controlled type 2 diabetes mellitus (T2DM) and to examine whether the neuropsychological deficits correlate with structural and functional brain alterations. Methods: We compared 25 subjects with T2DM aged 45–65 years with 25 control participants matched for age, gender, and educational level. The neuropsychological battery was designed to examine executive functions, attention, information processing speed, and verbal memory. Severity of depression was assessed using the Hamilton Depression Rating Scale and cardiovascular risk factors were assessed using the Framingham Cardiovascular Risk Profile Score. The …presence of at least one APOEε4 allele was determined. Reduced gray matter density was analyzed using voxel-based morphometry and brain glucose metabolic changes were assessed by 18 FDG-PET. Results: T2DM subjects had significantly lower scores than subjects without T2DM in the Trail-making Test B (p < 0.004), Color-Word Stroop test (p < 0.005), Semantic Fluency (p < 0.006), Digit-Symbol modalities test (p < 0.02), Text Recall from the Wechsler Memory Scale (p < 0.0001), Rey-Osterrieth Complex Figure-copy (p < 0.004), and delayed reproduction (p < 0.03). Worse executive functions and memory functioning correlated predominantly with less gray matter density and reduced glucose metabolism in the orbital and prefrontal cortex, temporal (middle gyrus, parahippocampus and uncus), and cerebellum regions (p < 0.001). Conclusions: T2DM subjects presented cognitive dysfunctions compared with controls. Clinical-neuroimaging correlations corresponded to brain changes (reduced gray matter density and glucose metabolism) mainly in fronto-temporal areas. Show more

Keywords: Cognition, dementia, magnetic resonance imaging, mild cognitive impairment, neuropsychology, positron emission tomography, type 2 diabetes mellitus

DOI: 10.3233/JAD-140702

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1337-1346, 2014

Authors: Álvarez, Antón | Aleixandre, Manuel | Linares, Carlos | Masliah, Eliezer | Moessler, Herbert

Article Type: Research Article

Abstract: Reduced brain-derived neurotrophic factor (BDNF) signaling is considered as a pathogenic event in early Alzheimer's disease (AD), but the influence of apathy and apolipoprotein E ε4 allele (APOE4) on serum BDNF values was not previously investigated in AD. We evaluated serum BDNF levels in AD, amnestic mild cognitive impairment (MCI), and control subjects. Baseline BDNF levels were similar in AD, MCI, and controls. AD patients having apathy showed lower BDNF values than patients without apathy (p < 0.05). After correction for the influence of apathy, APOE4 carriers showed lower BDNF levels (p < 0.01) and MMSE scores (p < 0.01) …than non-APOE4 carriers in the subgroup of AD females, but not in males. Significant (p < 0.05) positive correlations between BDNF values and MMSE scores were only observed in subgroups of AD males and of AD patients without apathy. These results are showing the association of apathy and APOE4 with reduced serum BDNF levels in AD, and are suggesting that BDNF reductions might contribute to the worse cognitive performance exhibited by AD apathetic patients and female APOE4 carriers. Show more

Keywords: Alzheimer's disease, apathy, apolipoprotein E ε4 allele, brain-derived neurotrophic factor, elderly control subjects, mild cognitive impairment, serum

DOI: 10.3233/JAD-140849

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1347-1355, 2014

Authors: Parcerisas, Antoni | Rubio, Sara E. | Muhaisen, Ashraf | Gómez-Ramos, Alberto | Pujadas, Lluís | Puiggros, Montserrat | Rossi, Daniela | Ureña, Jesús | Burgaya, Ferrán | Pascual, Marta | Torrents, David | Rábano, Alberto | Ávila, Jesús | Soriano, Eduardo

Article Type: Research Article

Abstract: Background: Although genome-wide association studies have shown that genetic factors increase the risk of suffering late-onset, sporadic Alzheimer’s disease (SAD), the molecular mechanisms responsible remain largely unknown. Objective: The aim of the study was to investigate the presence of somatic, brain-specific single nucleotide variations (SNV) in the hippocampus of SAD samples. Methods: By using bioinformatic tools, we compared whole exome sequences in paired blood and hippocampal genomic DNAs from 17 SAD patients and from 2 controls and 2 vascular dementia patients. Results: We found a remarkable number of SNVs in SAD brains (~575 per …patient) that were not detected in blood. Loci with hippocampus-specific (hs)-SNVs were common to several patients, with 38 genes being present in 6 or more patients out of the 17. While some of these SNVs were in genes previously related to SAD (e.g., CSMD1, LRP2), most hs-SNVs occurred in loci previously unrelated to SAD. The most frequent genes with hs-SNVs were associated with neurotransmission, DNA metabolism, neuronal transport, and muscular function. Interestingly, 19 recurrent hs-SNVs were common to 3 SAD patients. Repetitive loci or hs-SNVs were underrepresented in the hippocampus of control or vascular dementia donors, or in the cerebellum of SAD patients. Conclusion: Our data suggest that adult blood and brain have different DNA genomic variations, and that somatic genetic mosaicism and brain-specific genome reshaping may contribute to SAD pathogenesis and cognitive differences between individuals. Show more

Keywords: Alzheimer's disease, exome sequencing, somatic variations

DOI: 10.3233/JAD-140891

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1357-1382, 2014

Authors: Cheng, David | Spiro, Adena S. | Jenner, Andrew M. | Garner, Brett | Karl, Tim

Article Type: Research Article

Abstract: Impairments in cognitive ability and widespread pathophysiological changes caused by neurotoxicity, neuroinflammation, oxidative damage, and altered cholesterol homeostasis are associated with Alzheimer's disease (AD). Cannabidiol (CBD) has been shown to reverse cognitive deficits of AD transgenic mice and to exert neuroprotective, anti-oxidative, and anti-inflammatory properties in vitro and in vivo. Here we evaluate the preventative properties of long-term CBD treatment in male AβPPSwe /PS1ΔE9 (AβPP × PS1) mice, a transgenic model of AD. Control and AD transgenic mice were treated orally from 2.5 months of age with CBD (20 mg/kg) daily for 8 months. Mice were then assessed in the …social preference test, elevated plus maze, and fear conditioning paradigms, before cortical and hippocampal tissues were analyzed for amyloid load, oxidative damage, cholesterol, phytosterols, and inflammation. We found that AβPP × PS1 mice developed a social recognition deficit, which was prevented by CBD treatment. CBD had no impact on anxiety or associative learning. The prevention of the social recognition deficit was not associated with any changes in amyloid load or oxidative damage. However, the study revealed a subtle impact of CBD on neuroinflammation, cholesterol, and dietary phytosterol retention, which deserves further investigation. This study is the first to demonstrate CBD's ability to prevent the development of a social recognition deficit in AD transgenic mice. Our findings provide the first evidence that CBD may have potential as a preventative treatment for AD with a particular relevance for symptoms of social withdrawal and facial recognition. Show more

Keywords: Alzheimer's disease, amyloid load, behavior, cannabidiol, cholesterol, neuroinflammation, oxidative stress, phytosterol, social recognition memory, transgenic AβPPSwe/PS1ΔE9 mice

DOI: 10.3233/JAD-140921

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1383-1396, 2014

Authors: Muthaiyah, Balu | Essa, Musthafa M. | Lee, Moon | Chauhan, Ved | Kaur, Kulbir | Chauhan, Abha

Article Type: Research Article

Abstract: Previous in vitro studies have shown that walnut extract can inhibit amyloid-β (Aβ) fibrillization, can solubilize its fibrils, and has a protective effect against Aβ-induced oxidative stress and cellular death. In this study, we analyzed the effect of dietary supplementation with walnuts on learning skills, memory, anxiety, locomotor activity, and motor coordination in the Tg2576 transgenic (tg) mouse model of Alzheimer's disease (AD-tg). From the age of 4 months, the experimental groups of AD-tg mice were fed custom-mixed diets containing 6% walnuts (T6) or 9% walnuts (T9), i.e., equivalent to 1 or 1.5 oz, respectively, of walnuts per day in …humans. The control groups, i.e., AD-tg and wild-type mice, were fed a diet without walnuts (T0, Wt). These experimental and control mice were examined at the ages of 13–14 months by Morris water maze (for spatial memory and learning ability), T maze (for position discrimination learning ability), rotarod (for psychomotor coordination), and elevated plus maze (for anxiety-related behavior). AD-tg mice on the control diet (T0) showed memory deficit, anxiety-related behavior, and severe impairment in spatial learning ability, position discrimination learning ability, and motor coordination compared to the Wt mice on the same diet. The AD-tg mice receiving the diets with 6% or 9% walnuts (T6 and T9) showed a significant improvement in memory, learning ability, anxiety, and motor development compared to the AD-tg mice on the control diet (T0). There was no statistically significant difference in behavioral performance between the T6/T9 mice on walnuts-enriched diets and the Wt group on the control diet. These findings suggest that dietary supplementation with walnuts may have a beneficial effect in reducing the risk, delaying the onset, or slowing the progression of, or preventing AD. Show more

Keywords: Alzheimer's disease, antioxidants, dementia, inflammation, oxidative stress, transgenic mice, walnuts

DOI: 10.3233/JAD-140675

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1397-1405, 2014

Authors: Graham, Stewart F. | Nasaruddin, Muhammad Bin | Carey, Manus | Holscher, Christian | McGuinness, Bernadette | Kehoe, Patrick G. | Love, Seth | Passmore, Peter | Elliott, Christopher T. | Meharg, Andrew A. | Green, Brian D.

Article Type: Research Article

Abstract: Disease-, age-, and gender-associated changes in brain copper, iron, and zinc were assessed in postmortem neocortical tissue (Brodmann area 7) from patients with moderate Alzheimer's disease (AD) (n = 14), severe AD (n = 28), dementia with Lewy bodies (n = 15), and normal age-matched control subjects (n = 26). Copper was lower (20%; p < 0.001) and iron higher (10–16%; p < 0.001) in severe AD compared with controls. Intriguingly significant Group*Age interactions were observed for both copper and iron, suggesting gradual age-associated decline of these metals in healthy non-cognitively impaired individuals. Zinc was unaffected in any disease pathologies …and no age-associated changes were apparent. Age-associated changes in brain elements warrant further investigation. Show more

Keywords: Alzheimer's disease, brain, copper, dementia, iron, Lewy body, trace elements, zinc

DOI: 10.3233/JAD-140684

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1407-1413, 2014

Authors: Domingues, Sara C. | Konietzko, Uwe | Henriques, Ana Gabriela | Rebelo, Sandra | Fardilha, Margarida | Nishitani, Hideo | Nitsch, Roger M. | da Cruz e Silva, Edgar F. | da Cruz e Silva, Odete A.B.

Article Type: Research Article

Abstract: Proteolytic processing of the amyloid-β protein precursor (AβPP) occurs via alternative pathways, culminating with the production of the AβPP intracellular domain (AICD). AICD can translocate to the nucleus and regulate transcription, but its activity is modulated by interactions with other proteins. In the nucleus, AICD, FE65, and Tip60 associate into AFT complexes, which are targeted to nuclear spots which correspond to transcription factories. Here we report that RanBP9 interacts with the cytoplasmic domain of AβPP, through the NPXY internalization motif. Moreover, RanBP9 interaction with Tip60 is also described. The RanBP9-Tip60 interaction dramatically relocated RanBP9 from a widespread cellular distribution to …nuclear speckles. AβPP processing is a central aspect in determining the protein's function and that of its resulting proteolytic fragments, among them AICD. The latter results from the amyloidogenic pathway and is the peptidic species predominantly involved in nuclear signaling. Of note RanBP9 transfection was previously demonstrated to increase amyloid-β generation. Here we show that RanBP9 relocates AICD to the Tip60-enriched nuclear speckles, and prevented the formation of nuclear spots formation, having therefore a negative effect on AICD mediated nuclear signaling and consequently AFT complex formation. Furthermore, by transfecting cells with increasing amounts of RanBP9, the expression of AICD-regulated genes, including AβPP itself, was reduced. Given the data presented, one can deduce that RanBP9 has an inhibitory regulatory effect on AICD-mediated transcription and the effect is mediated by relocating AICD away from transcription factories. Show more

Keywords: Alzheimer's disease, amyloid-β precursor protein, AβPP, AFT spots, nuclear speckles, Fe65, nuclear signaling, RanBPM

DOI: 10.3233/JAD-132495

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1415-1433, 2014

Authors: Nägga, Katarina | Hansson, Oskar | van Westen, Danielle | Minthon, Lennart | Wennström, Malin

Article Type: Research Article

Abstract: Hyaluronic acid (HA) has been shown to affect angiogenesis and the function of the blood-brain barrier, and a crucial role for HA in atherosclerosis has been described. We have recently demonstrated changes in the levels of HA in cerebrospinal fluid (CSF) in patients with Alzheimer's disease (AD) with documented vascular alterations. To further investigate if the level of HA in CSF can be used as a clinical diagnostic biomarker to identify vascular pathology in dementia, we analyzed the levels of HA in the CSF of patients with vascular dementia (VaD) (n = 46), AD (n = 45), and controls without …dementia (n = 26). In line with our previous data, we found significantly increased levels of HA in CSF from patients with VaD compared with controls, whereas the levels of HA in patients with AD were found to be unaltered compared with controls and patients with VaD. We also detected increased levels of HA in individuals with vascular changes determined as significant white matter changes or previous infarction on cranial computed tomography or magnetic resonance imaging, compared with individuals without these findings. Furthermore, we found a significant positive correlation between the levels of HA and the CSF/serum albumin ratio, an indicator of blood-brain barrier integrity, in patients with VaD and AD, supporting the role of HA in vascular changes in the brain. Our results indicate a potential diagnostic value for the detection of vascular brain changes in dementia using CSF levels of HA, but emphasize the importance of further development of more sensitive HA assays. Show more

Keywords: Biomarker, cerebrospinal fluid, glycocalyx, hyaluronic acid, vascular dementia

DOI: 10.3233/JAD-141200

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1435-1441, 2014

Authors: Rahman, Tasnim | Davies, Danielle S. | Tannenberg, Rudi K. | Fok, Sandra | Shepherd, Claire | Dodd, Peter R. | Cullen, Karen M. | Goldsbury, Claire

Article Type: Research Article

Abstract: Background: Imaging of human brain as well as cellular and animal models has highlighted a role for the actin cytoskeleton in the development of cell pathology in Alzheimer’s disease (AD). Rods and aggregates of the actin-associated protein cofilin are abundant in grey matter of postmortem AD brain and rods are found inside neurites in animal and cell models of AD. Objective: We sought further understanding of the significance of cofilin rods/aggregates to the disease process: Do rods/aggregates correlate with AD progression and the development of hallmark neurofibrillary tangles and neuropil threads? Are cofilin rods/aggregates found in the same …neurites as hyperphosphorylated tau? Methods: The specificity of rods/aggregates to AD compared with general aging and their spatial relationship to tau protein was examined in postmortem human hippocampus, inferior temporal cortex, and anterior cingulate cortex. Results: The presence of cofilin rods/aggregates correlated with the extent of tau pathology independent of patient age. Densities of rods/aggregates were fourfold greater in AD compared with aged-matched control brains and rods/aggregates were significantly larger in AD brain. We did not find evidence for our hypothesis that intracellular cofilin rods are localized to tau-positive neuropil threads. Instead, data suggest the involvement of microglia in the clearance of cofilin rods/aggregates and/or in their synthesis in and around amyloid plaques and surrounding neuropil. Conclusion: Cofilin rods and aggregates signify events initiated early in the pathological cascade. Further definition of the mechanisms leading to their formation in the human brain will provide insights into the cellular causes of AD. Show more

Keywords: Actin, amyloid plaque, cofilin protein, cytoskeleton, microglia, neurofibrillary tangles, neuropil threads, tau protein

DOI: 10.3233/JAD-140393

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1443-1460, 2014

Authors: Gallucci, Maurizio | Battistella, Giuseppe | Bergamelli, Cristina | Spagnolo, Pierpaolo | Mazzuco, Stefano | Carlini, Antonio | Di Giorgi, Enrico | Boldrini, Paolo | Pilotto, Alberto

Article Type: Research Article

Abstract: Background: The Multidimensional Prognostic Index (MPI) based on a comprehensive geriatric assessment has been developed to predict mortality in hospitalized elderly patients. The Treviso Dementia (TREDEM) Study is an observational prospective cohort study of 1,364 outpatients evaluated at the Cognitive Impairment Center in Treviso, Italy from 2000 to January 2010. Objective: To use the MPI in the TREDEM outpatient setting to assess the correlation of MPI with mortality and hospitalizations for acute cases that occurred after the date of assessment. Methods: MPI was consecutively applied to the last 340 of 1,364 outpatients who were evaluated at …the Center from 2008 to January 2010, after the first publication of MPI index in 2008. Participants’ mortality was verified by linking the cohort with Registries of Municipalities, National Register of Revenue Authorities, and Nominal Register of Causes of Death. Data about hospitalizations for acute cases that occurred within 12 months after the date of assessment were obtained from all Italian hospitals. A Cox regression method was used to investigate the effect of MPI upon mortality and hospitalizations, also considering confounder factors such as age and gender. Results: 114 men and 226 women, aged 52.1–99 years (mean age 80.4 years), were studied and had an MPI mean of 0.41. On 15 February 2013, 100 were deceased, and average hospitalizations for acute cases were 0.3, days 3.8. For MPI scores between 0 and 1, the increase in the probability of death was more than nine times (odds: 9.53 p = 0.0002) and of hospitalization was more than six times (odds: 6.50, p = 0.0079). Conclusion: MPI discloses the risk of death and of hospitalizations for acute cases in outpatients affected by cognitive impairment. Show more

Keywords: Cognitive impairment, hospitalizations, mortality, multidimensional prognostic index, outpatients, TREDEM

DOI: 10.3233/JAD-140516

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1461-1468, 2014

Authors: Bittner, Daniel M. | Wieseler, Isabel | Wilhelm, Helmut | Riepe, Matthias W. | Müller, Notger G.

Article Type: Research Article

Abstract: It was investigated whether alterations of the pupil's light reflex might reflect Alzheimer's disease (AD) pathology. Changes in the pupil's system might be expected due to AD pathology present in the oculomotor system of the Edinger-Westphal nucleus, and a cholinergic deficit caused by degeneration of the nucleus basalis Meynert. A rather new method of repetitive light stimulation was applied assessing variations in pupil size, latency, and amplitude over time. We analyzed 44 healthy controls, 42 subjects with mild cognitive impairment (MCI), and 66 AD patients. AD and MCI showed a less pronounced pupil size decrease and amplitude increase over time …than controls. A higher MMSE was associated with a higher increase of relative amplitude and greater decrease of latency in AD and MCI, and absolute amplitude increase in AD alone. Pupil size increase correlated with cerebrospinal fluid markers in AD. Summarized pupil light reflex is not stable under repetitive stimulation, but changes systematically and less pronounced in AD and MCI. Thus repetitive stimulation of the pupil's response potentially indicates AD pathology. Show more

Keywords: Alzheimer's disease, amyloid-β 1-42, cerebrospinal fluid, mild cognitive impairment, parasympathetic system, pupil light reflex, repetitive stimulation, sympathetic inhibition, tau

DOI: 10.3233/JAD-140969

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1469-1477, 2014

Article Type: Other

DOI: 10.3233/JAD-140971

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1479-1486, 2014

Article Type: Other

DOI: 10.3233/JAD-140970

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1487-1488, 2014

Article Type: Other

DOI: 10.3233/JAD-2014-42434

Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1489-1502, 2014