Journal of Alzheimer's Disease - Volume 38, issue 3

Authors: Gallucci, Maurizio | Zanardo, Andrea | Bendini, Matteo | Di Paola, Francesco | Boldrini, Paolo | Grossi, Enzo

Article Type: Research Article

Abstract: Background: The role of folate and homocysteine in brain atrophy associated with Alzheimer’s disease is not completely understood. Objective: The aim of this study was to investigate the relationships between serum folate and homocysteine levels and the degree of cortical-subcortical and hippocampal atrophy in a first relatively preliminary sample of the Treviso Dementia (TREDEM) study using a potent data mining method. Methods: Physiological data, biochemical parameters, clinical assessment data, brain atrophy severity assessed with CT scans, and neuropsycological and disability data were assessed in a group of 232 outpatients (93 men and 139 women, aged 40.2–100 …years) enrolled in the TREDEM study carried out in Treviso (Italy). A semantic connectivity map obtained through the Auto-CM system, a fourth generation artificial neural network (ANN), was used to offer some insight regarding the complex biological connections between the studied variables and the degree of brain atrophy. Results: Close associations between low serum folate levels and severe cortical-subcortical atrophy along with severe hippocampal atrophy measured by the width of the temporal horns of lateral ventricles were found. We also showed an association between high homocysteine levels and severe cortical-subcortical and hippocampal atrophy. Conclusion: The role of folate, which is inversely associated with the severity of brain atrophy, was confirmed. Our results also confirm the association between high homocysteine levels and severe cortical-subcortical and hippocampal atrophy. Auto-CM ANN is able to highlight associations sometimes visible only in longitudinal studies through intelligent data mining of a cross-sectional study. Show more

Keywords: Auto-CM system, brain atrophy, hippocampal atrophy, homocysteine, serum folate, TREDEM

DOI: 10.3233/JAD-130956

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 581-587, 2014

Authors: Ren, Yan | Lin, Wen-Lang | Sanchez, Laura | Ceballos, Carolina | Polydoro, Manuela | Spires-Jones, Tara L. | Hyman, Bradley T. | Dickson, Dennis W. | Sahara, Naruhiko

Article Type: Research Article

Abstract: Tau belongs to the microtubule-associated family of proteins that maintain cytoskeletal structure by regulating microtubule dynamics. In certain neurodegenerative diseases termed tauopathies, tau is abnormally phosphorylated and accumulates as filamentous inclusions. Transgenic mouse models that overexpress human tau have been widely used to investigate tau pathogenesis. Although many studies have attempted to elucidate the pathological function of transgenic human tau, it remains unknown whether endogenous mouse tau is involved in disease progression. Here we generated an mTau antibody that selectively recognizes mouse and rat tau, but not human tau. In rTg4510 tau transgenic mice, we identified a higher molecular weight …mouse tau (~60-kDa) in sarkosyl-insoluble fractions. mTau antibody started to recognize intracellular aggregates and thread-like structures in 4- to 6-month-old rTg4510 mice. Tau inclusions appeared earlier, being detected in 2.5-month-old rTg4510 mice with MC1 antibody. Immunoelectron microscopy confirmed the presence of filamentous aggregates of mouse tau, which were abundant in oligodendrocytes but rare in neurons. Mouse tau inclusions in oligodendrocytes were confirmed by double-labeling with an oligodendrocyte marker. Our data indicate that mouse tau has potential aggregation properties in neurons and non-neurons. The mTau antibody will be useful for investigating the role of mouse tau in mouse models of tauopathy. Show more

Keywords: Antibody, mouse tau, oligodendrocytes, tau protein, tauopathy, transgenic mice

DOI: 10.3233/JAD-130986

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 589-600, 2014

Authors: Honjo, Yasuyuki | Horibe, Tomohisa | Torisawa, Aya | Ito, Hidefumi | Nakanishi, Aki | Mori, Hiroshi | Komiya, Tohru | Takahashi, Ryosuke | Kawakami, Koji

Article Type: Research Article

Abstract: Amyloid plaques and neurofibrillary tangles (NFTs) are the major pathological characteristics of Alzheimer's disease (AD). NFTs are composed of tubular filaments and paired helical filaments containing polymerized hyperphosphorylated tau protein. Another feature of AD is excessive generation of nitric oxide (NO). Protein disulfide isomerase (PDI) is a chaperon protein located in the endoplasmic reticulum (ER). It was recently reported that NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leading to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. In addition, we previously reported the presence of PDI-immunopositive NFTs in AD. Here, we found that protein disulfide isomerase …P5 (P5), which is a member of the PDI protein family, was co-localized with tau in NFTs. To our knowledge, this is the first report of P5-immunopositive inclusion in AD. Furthermore, we showed that S-nitrosylated P5 was present and the expression level of P5 was decreased in AD brains compared with that of control brains. We also demonstrated that the knock-down of PDI or P5 by siRNA could affect the viability of SH-SY5Y cells under ER stress. Previously, the observation of S-nitrosylated PDI in AD was reported. NO may inhibit P5 by inducing S-nitrosylation in the same manner as PDI, which inhibits its enzymatic activity allowing protein misfolding to occur in AD. The accumulation of misfolded proteins induces ER stress and may cause apoptosis of neuronal cells through S-nitrosylation and down-regulation of PDI and P5 in AD. Show more

Keywords: Alzheimer's disease, endoplasmic reticulum stress, misfolding, neurofibrillary tangle, nitric oxide, protein disulfide isomerase, protein disulfide isomerase P5, S-nitrosylation, tau

DOI: 10.3233/JAD-130632

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 601-609, 2014

Authors: Grant, William B.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) rates in Japan and developing countries have risen rapidly in recent years. Researchers have associated factors such as the Western diet, obesity, alcohol consumption, and smoking with risk of AD. Objective: This paper evaluates whether the dietary transition might explain the rising trend of AD prevalence in Japan and in developing countries, evaluating other factors when possible. Methods: This study used two approaches to see whether dietary or other changes could explain AD trends in Japan and developing countries. One approach involved comparing trends of AD in Japan with changes in national …dietary supply factors, alcohol consumption, and lung cancer mortality rates from zero to 25 years before the prevalence data. The second compared AD prevalence values for eight developing countries with dietary supply factors from zero to 25 years before the prevalence data. Results: For Japan, alcohol consumption, animal product, meat and rice supply, and lung cancer rates correlated highly with AD prevalence data, with the strongest correlation for a lag of 15–25 years. In the eight-country study, total energy and animal fat correlated highly with AD prevalence data, with a lag of 15–20 years. Mechanisms to explain the findings include increased obesity for the eight countries, and increases in cholesterol, saturated fat, and iron from increases in animal products and meat supply for Japan. Conclusion: Evidently AD rates will continue rising in non-Western countries for some time unless we address major risk factors involving diet, obesity, and smoking. Show more

Keywords: Alzheimer's disease, dementia, dietary supply, iron, meat, nutrition transition, obesity, rice, zinc

DOI: 10.3233/JAD-130719

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 611-620, 2014

Authors: Xu, Wenjin | Xu, Feng | Anderson, Maria E. | Kotarba, AnnMarie E. | Davis, Judianne | Robinson, John K. | Van Nostrand, William E.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is an age-dependent neurodegenerative condition that causes a progressive decline in cognitive function. Accumulation of amyloid β-protein (Aβ) in the brain is a prominent feature of AD and related disorders. However, the levels of Aβ accumulation alone are not a reliable predictor of cognitive deficits. Aβ accumulates in AD brain in the form of parenchymal amyloid plaques and cerebral vascular deposits. Although both types of lesions can contribute to cognitive decline, their temporal impact remains unclear. Moreover, cerebral microvascular pathology is identified as an early driver of cognitive impairment. Here for the first time, we compared two …transgenic mouse strains, Tg-5xFAD and Tg-SwDI, which exhibit similar onset and anatomical accumulation of Aβ, but with distinct parenchymal and microvascular compartmental deposition, respectively, to assess their impact on cognitive impairment. Cohorts of each line were tested at 3 and 6 months of age to assess the relationship between spatial working memory performance and quantitative pathology. At 3 months of age, Tg-SwDI mice with onset of cerebral microvascular amyloid were behaviorally impaired, while the Tg-5xFAD, which had disproportionately higher levels of total Aβ, soluble oligomeric Aβ, and parenchymal amyloid were not. However, at 6 months of age, behavioral deficits for both groups of transgenic mice were evident, as the levels of Aβ pathologies in the Tg-5xFAD accumulated to extremely high amounts. The present findings suggest early-onset cerebral microvascular amyloid deposition, that precedes high parenchymal levels of Aβ, may be an important early factor in the development of cognitive deficits. Show more

Keywords: Amyloid-β protein, cerebral microvascular, cognitive impairment, parenchymal, pathology, transgenic mice

DOI: 10.3233/JAD-130758

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 621-632, 2014

Authors: Tan, Meng-Shan | Yu, Jin-Tai | Jiang, Teng | Zhu, Xi-Chen | Guan, Hua-Shi | Tan, Lan

Article Type: Research Article

Abstract: Progressively increased proinflammatory status is a major characteristic of the aging process and associated with age-related diseases such as Alzheimer's diseases (AD). However, the regulation and role of common proinflammatory cytokines, including interleukin-12 (IL-12) and IL-23, in the aged brain are still unclear. Using the senescence-accelerated mouse prone-8 (SAMP8) model, we screened the cerebral expression of IL-12/23 in 3-, 7-, and 11-month-old mice and observed that their levels in the brain were upregulated during aging. To further examine whether the heightened activation of inflammatory cytokines may contribute to age-related brain dysfunction, we employed direct in vivo infusion of nonviral small …interfering RNA (siRNA) to knock down the common IL-12/23 signaling subunit p40 in the brain. We found that these p40-deficient mice had significantly decreased cerebral amyloid-β levels, reduced synaptic and neuronal loss, and reversed cognitive impairments. Furthermore, in vivo delivery of a neutralizing p40-specific antibody likewise ameliorated AD-associated pathology and cognitive deficits in SAMP8 mice. Thus, our data indicate that the upregulated cerebral IL-12/23 during aging is involved in age-associated brain dysfunction and point to the modulation of IL-12/23 signaling molecule p40 as a promising strategy for the development of an AD therapy. Show more

Keywords: Aging, Alzheimer's disease, amyloid-β, IL-12, IL-23, memory impairment, SAMP8

DOI: 10.3233/JAD-131148

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 633-646, 2014

Authors: Diaz-de-Grenu, Lara Z. | Acosta-Cabronero, Julio | Chong, Yao Feng Victor | Pereira, Joao M.S. | Sajjadi, Seyed A. | Williams, Guy B. | Nestor, Peter J.

Article Type: Research Article

Abstract: Voxel-based morphometry (VBM) and cortical thickness measurement are common techniques to identify regional atrophy in neurodegenerative diseases such as Alzheimer's disease (AD). Because studies employing these methods draw conclusions regarding patterns of regional cortical degeneration, it is important to be aware of their possible limitations. To evaluate the effect of different VBM versions, we performed voxel-based analyses through successive versions—from SPM99 to SPM8—as well as FSL-VBM on n = 20 AD patients and n = 20 controls. Reproducibility was assessed in an independent sample, again of n = 20 per group, from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Further, …we tested the hypothesis that VBM can sensitively detect hippocampal atrophy, but is relatively insensitive to changes in the cortical ribbon, by contrasting VBM with FreeSurfer cortical thickness measurements. The results with both datasets confirmed that VBM preferentially identifies grey matter lesions in the mesial temporal lobe but is largely insensitive to isocortical atrophy. In contrast, FreeSurfer identified thinning of cortical ribbon association cortex more significant in post- rather than pre-Rolandic areas and with relative preservation of primary sensory-motor regions—in other words precisely as would be expected in AD. The results highlight a bias that VBM has toward detecting mesial temporal lobe atrophy. This finding has important implications for interpretation of clinical and cognitive studies in AD. Show more

Keywords: Alzheimer's disease, atrophy, computer-assisted, diagnosis, image interpretation, magnetic resonance imaging

DOI: 10.3233/JAD-130362

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 647-659, 2014

Authors: Razlighi, Qolamreza R. | Stallard, Eric | Brandt, Jason | Blacker, Deborah | Albert, Marilyn | Scarmeas, Nikolaos | Kinosian, Bruce | Yashin, Anatoliy I. | Stern, Yaakov

Article Type: Research Article

Abstract: Background: The ability to predict the length of time to death and institutionalization has strong implications for Alzheimer’s disease patients and caregivers, health policy, economics, and the design of intervention studies. Objective: To develop and validate a prediction algorithm that uses data from a single visit to estimate time to important disease endpoints for individual Alzheimer’s disease patients. Method: Two separate study cohorts (Predictors 1, N = 252; Predictors 2, N = 254), all initially with mild Alzheimer’s disease, were followed for 10 years at three research centers with semiannual assessments that included cognition, functional capacity, …and medical, psychiatric, and neurologic information. The prediction algorithm was based on a longitudinal Grade of Membership model developed using the complete series of semiannually-collected Predictors 1 data. The algorithm was validated on the Predictors 2 data using data only from the initial assessment to predict separate survival curves for three outcomes. Results: For each of the three outcome measures, the predicted survival curves fell well within the 95% confidence intervals of the observed survival curves. Patients were also divided into quintiles for each endpoint to assess the calibration of the algorithm for extreme patient profiles. In all cases, the actual and predicted survival curves were statistically equivalent. Predictive accuracy was maintained even when key baseline variables were excluded, demonstrating the high resilience of the algorithm to missing data. Conclusion: The new prediction algorithm accurately predicts time to death, institutionalization, and need for full-time care in individual Alzheimer’s disease patients; it can be readily adapted to predict other important disease endpoints. The algorithm will serve an unmet clinical, research, and public health need. Show more

Keywords: Alzheimer's disease, full-time care, grade of membership model, nursing home, prediction algorithm, time to death

DOI: 10.3233/JAD-131142

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 661-668, 2014

Authors: Kamminga, Jody | O'Callaghan, Claire | Hodges, John R. | Irish, Muireann

Article Type: Research Article

Abstract: Background: Prospective memory (PM) is the ability to remember to execute an intended action either at a future time (Time-based PM) or when a specific event occurs (Event-based PM). Previous studies demonstrate impaired PM in Alzheimer’s disease (AD); however, the status of PM in frontotemporal dementia (FTD) remains unknown. Objective: To examine PM performance and its associated cognitive mechanisms, in two subtypes of FTD: semantic dementia (SD) and the behavioral variant of FTD (bvFTD), in comparison with matched AD and control participants. Methods: Twenty-four dementia patients (SD = 8; bvFTD = 8; AD = 8) and …12 age- and education-matched controls underwent a shortened version of the Cambridge Behavioural Prospective Memory Test, as well as a standard neuropsychological test battery. Results: Compared to controls, SD patients exhibited preserved Time-based PM in the context of impaired Event-based PM, with the latter strongly associated with deficits in semantic processing. In contrast, bvFTD and AD patients demonstrated global PM impairments irrespective of subscale, which strongly correlated with deficits in delayed episodic retrieval for both groups. Caregiver reports of stereotypical behaviors were associated with compromised Event-based PM in SD and Time-based PM in bvFTD, with no such relationship evident in AD. Conclusion: This is the first study to investigate prospective memory in FTD syndromes. A relative sparing of Time-based PM was observed in SD, in contrast with global PM deficits in bvFTD. Disrupted PM processing was found to correlate with stereotypical behaviors in FTD syndromes, a finding that we suggest is worthy of further investigation. Show more

Keywords: Aging, alzheimer's disease, behavioral variant frontotemporal dementia, episodic memory, neuropsychological tests, prospective memory, semantic dementia

DOI: 10.3233/JAD-131118

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 669-679, 2014

Authors: Stefanova, Natalia A. | Muraleva, Natalia A. | Skulachev, Vladimir P. | Kolosova, Nataliya G.

Article Type: Research Article

Abstract: We previously showed that mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyltriphenylphosphonium) at nanomolar concentrations is capable of preventing and slowing down some cerebral dysfunctions in accelerated-senescence OXYS rats. Here we demonstrate that OXYS rats develop behavior, learning, and memory deficits against a background of neurodegeneration signs detected by magnetic resonance tomography and amyloid-β (Aβ) pathology similar to those seen in Alzheimer's disease (AD). Long-term treatment with SkQ1 (250 nmol/kg body weight daily from the age of 1.5 to 23 months) reduced the age-related alterations in behavior and spatial memory deficit in Morris water maze in OXYS and Wistar rats. Furthermore, this is the …first report that SkQ1 treatment slows down pathological accumulation of AβPP, Aβ, and hyperphosphorylation of tau-protein in OXYS rats, as well as age-dependent changes in healthy Wistar rats. Our results support the possibility of using the OXYS strain as a rat model of AD-like pathology. It seems probable that the mitochondria-targeted antioxidant SkQ1 can be a good prophylactic strategy to maintain brain health and to treat AD. Show more

Keywords: Alzheimer's disease, brain aging, mitochondria-targeted antioxidant SkQ1, senescence-accelerated OXYS rats

DOI: 10.3233/JAD-131034

Citation: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 681-694, 2014