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

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