Journal of Alzheimer's Disease - Volume 47, issue 3

Authors: Floris, Gianluca | Di Stefano, Francesca | Cherchi, Maria Valeria | Costa, Gianna | Marrosu, Francesco | Marrosu, Maria Giovanna

Article Type: Short Communication

Abstract: Cerebral microbleeds (CMB) might reflect specific underlying vascular pathologies like cerebral amyloid angiopathy (CAA). In the present study we report the gradient-echo MRI pattern of two siblings with P284S PSEN1 mutation. T2* gradient-echo images of the two subjects demonstrated multiple microbleeds in lobar regions. The role and causes of CMB in sporadic Alzheimer’s disease (AD) patients have not been clearly established and useful contributions could derive from familial AD studies. Furthermore, since CAA is a potential risk factor for developing adverse events in AD immunization trials, the identification in vivo of CAA through non-invasive MRI methods could be useful …to monitoring side effects. Show more

Keywords: Alzheimer’s disease, amyloid angiopathy, ARIA, cerebral microbleeds, PSEN1 mutation

DOI: 10.3233/JAD-150165

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 535-538, 2015

Authors: Tiepolt, Solveig | Patt, Marianne | Hoffmann, Karl-Titus | Schroeter, Matthias L. | Sabri, Osama | Barthel, Henryk

Article Type: Short Communication

Abstract: The revised NIA-AA diagnostic criteria for Alzheimer’s disease (AD) and mild cognitive impairment (MCI) due to AD make use of amyloid pathology and neurodegeneration biomarkers which increase the diagnostic confidence in the majority of patients. However, in daily praxis, cases with conflicting biomarker constellations occur. A MCI subject underwent neuropsychological testing supplemented by FDG and amyloid PET/MRI as well as CSF sampling. In this subject, the biomarkers of Aβ deposition were negative. [18 F]FDG PET, however, showed an AD-typical hypometabolism. Further studies are required to determine frequency and relevance of cases with neurodegeneration-first biomarker constellations to improve our understanding on …pathogenesis and diagnosis of AD. Show more

Keywords: Alzheimer’s disease, amyloid, FDG, mild cognitive impairment, PET

DOI: 10.3233/JAD-150163

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 539-543, 2015

Authors: Peters-Libeu, Clare | Campagna, Jesus | Mitsumori, Michael | Poksay, Karen S. | Spilman, Patricia | Sabogal, Alex | Bredesen, Dale E. | John, Varghese

Article Type: Research Article

Abstract: Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by the enzyme BACE1 (BACE) is the initial step in production of amyloid-β peptide (Aβ), and as such has been a major target of Alzheimer’s disease (AD) drug discovery efforts. Overproduction of Aβ results in neuronal cell death and accumulation of amyloid plaques in AD and in traumatic brain injury, and is also associated with stroke due to cerebral amyloid angiopathy. Herein we report for the first time that sAβPPα , the product of the cleavage of AβPP by α -secretase, is a potent endogenous direct inhibitor of the BACE enzyme, and …that its inhibition is likely by an allosteric mechanism. Furthermore, using small-angle X-ray scattering, we show that sAβPPβ, which is identical to sAβPPα except for a 16-amino acid truncation at the carboxy terminus, adopts a completely different structure than sAβPPα and does not inhibit BACE. Our data thus reveal a novel mechanistic role played by sAβPPα in regulating overproduction of Aβ and restoring neuronal homeostasis and neuroprotection. Identification of sAβPPα as a direct BACE inhibitor may lead to design of new therapeutics targeting pathologies associated with overproduction of Aβ. Show more

Keywords: Aβ, sAβPPα, sAβPPβ, allosteric, BACE, BACE1, endogenous, inhibitor, SAXS

DOI: 10.3233/JAD-150282

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 545-555, 2015

Authors: Khatoon, Sabiha | Chalbot, Sonia | Bolognin, Silvia | Puoliväli, Jukka | Iqbal, Khalid

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the single major cause of dementia in middle- to old-age individuals, and, as of yet, no disease-modifying therapeutic drug is available for its treatment. A major obstacle in the successful development of disease-modifying therapeutic drugs has been the lack of suitable animal models of the sporadic form of AD as well as a biomarker that can be used both for therapeutic preclinical studies and for human clinical trials. Previously we showed neurogenesis and neuronal plasticity deficits and cognitive impairment and their rescue with a neurotrophic peptidergic compound, DGGLA G named P021, in aged Fisher rats. Here …we show that P021 is blood-brain-barrier-permeable, and chronic oral treatment with this compound can reduce the brain level of total tau in the aged rats. Furthermore, cerebrospinal fluid (CSF) levels of both tau and Aβ/AβPP are elevated in the aged animals, and chronic treatment with P021 can reduce tau but not Aβ/AβPP to that of the levels found in young adult rats. Importantly, P021 does not induce any detectable immune reaction in rats. Collectively, these studies show the therapeutic potential of P021 as a disease-modifying compound and the suitability of the aged Fisher rats as a model of cerebral aging in which the therapeutic efficacy of a tau-reducing compound can be monitored in the CSF. Show more

Keywords: Aged Fisher rat, Alzheimer’s disease, cerebral aging, cerebrospinal fluid, ELISA, rat, tau protein

DOI: 10.3233/JAD-142799

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 557-564, 2015

Authors: Wang, Zi-Xuan | Tan, Lan | Wang, Hui-Fu | Ma, Jing | Liu, Jinyuan | Tan, Meng-Shan | Sun, Jia-Hao | Zhu, Xi-Chen | Jiang, Teng | Yu, Jin-Tai

Article Type: Research Article

Abstract: To evaluate whether iron, zinc, and copper levels in serum are disarranged in Alzheimer’s disease (AD), we performed meta-analyses of all studies on the topic published from 1984 to 2014 and contextually carried out a replication study in serum as well. Our meta-analysis results showed that serum zinc was significantly lower in AD patients. Our replication and meta-analysis results showed that serum copper was significantly higher in AD patients than in healthy controls, so our findings were consistent with the conclusions of four previously published copper meta-analyses. Even if a possible role of iron in the pathophysiology of the disease …could not be ruled out, the results of our meta-analysis showed no change of serum iron levels in AD patients, but this conclusion was not robust and requires further investigation. The meta-regression analyses revealed that in some studies, differences in serum iron levels could be due to the different mean ages, while differences in zinc levels appeared to be due to the different sex ratios. However, the effect of sex ratio on serum zinc levels in our meta-analysis is subtle and needs further confirmation. Also, diverse demographic terms and methodological approaches appeared not to explain the high heterogeneity of our copper meta-analysis. Therefore, when investigating trace elements, covariants such as age and sex have to be taken into account in the analyses. In the light of these findings, we suggest that the possible alteration of serum zinc and copper levels are involved in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, meta-analysis, serum copper, serum iron, serum zinc

DOI: 10.3233/JAD-143108

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 565-581, 2015

Authors: Suvorina, Mariya Yu. | Selivanova, Olga M. | Grigorashvili, Elizaveta I. | Nikulin, Alexey D. | Marchenkov, Victor V. | Surin, Alexey K. | Galzitskaya, Oxana V.

Article Type: Research Article

Abstract: The aim of this study was to investigate the process of amyloidogenesis of amyloid-β (Aβ)42 peptide, by means of fluorescence spectroscopy, electron microscopy, X-ray diffraction, and mass spectrometry. It has been repeatedly reported in the literature that the process of fibril formation by Aβ 42 peptide depends considerably not only upon the specific conditions (ionic conditions, pH, temperature, mixing, etc.), as well as the manufacturing route (synthetic or recombinant), but also on the methods of synthesis and purification. We have, for the first time, systematically analyzed samples of Aβ 42 peptide supplied by five different companies (Anaspec, …Invitrogen, Enzo, Sigma-Aldrich, and SynthAssist) and obtained evidence of significant variability, including lot to lot variations. All studied samples formed amyloid-like fibrils at pH3-6, and the fibrils contained cross-β structures. Samples from Anaspec, Invitrogen, and Enzo formed one particular type of amyloid-like fibrils, while the samples from Sigma-Aldrich and SynthAssist formed another distinct type of fibrils. The observed polymorphism emphasizes the capacity of the Aβ 42 peptide to act as a prion agent with varying structural characteristics. The presented data have allowed us to propose a possible mechanism of formation of amyloid-like fibrils. Show more

Keywords: Aβ 42 peptide, Alzheimer’s disease, amyloid fibril, electron microscopy, mass spectroscopy, oligomer, prion-like behavior, protofibril

DOI: 10.3233/JAD-150147

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 583-593, 2015

Authors: Li, Lisha | Peng, Yahui | Hui, Yang | Zhang, Shuai | Zhou, You | Li, Dan | Li, Jihong | Si, Zizhen | Li, Jing | Wang, Dayong | Li, Yanze | Dong, Min | Gao, Xu

Article Type: Research Article

Abstract: The expression of heme oxygenase 1 (HO-1) in the cortex and hippocampus is higher in Alzheimer’s disease (AD) and mild cognitive impairment patients than healthy individuals, and epidemiological studies suggest that HO-1 is an important factor for AD. However, its influence on nerve function is poorly understood. Here, we studied the effect of the overexpression of HO-1 on the cognitive and synaptic plasticity in 3-month-old mice. We found that the overexpression of HO-1 induced spatial learning and memory deficits with an apparent decrease of AMPKR, NMDAR, postsynaptic density protein 95, synapsin I, synaptophysin, and microtubule-associated protein 2, all of which …are memory-related synaptic proteins. Concurrently, HO-1 could co-express and induce the aggregation of Aβ 42 and Aβ oligomer in the hippocampus area. Additionally, our research is the first to demonstrate that HO-1 changes the morphology of the synapse to impair the neural circuit. These results indicate that the overexpression of HO-1 can damage synaptic plasticity in early stages to induce AD-like pathology and cognitive abnormality in mice. Show more

Keywords: Alzheimer’s disease, amyloid-β oligomer, dendritic spine, heme oxygenase 1, synaptic plasticity

DOI: 10.3233/JAD-150027

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 595-608, 2015

Authors: Nakano, Yumiko | Matsuzono, Kosuke | Yamashita, Toru | Ohta, Yasuyuki | Hishikawa, Nozomi | Sato, Kota | Deguchi, Kentaro | Abe, Koji

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is one of the most significant diseases affecting an increasingly aging society. Objective: To determine the long-term efficacy of galantamine treatment in a Japanese population. Methods: We performed “Okayama Galantamine Study (OGS)” to retrospectively analyze the clinical effects of galantamine in 279 AD patients using 7 batteries for assessing dementia at baseline, 3, 6, 12, and 24 months. We further analyzed the effects of galantamine based on gender and the severity of their baseline cognitive, affective, and activity of daily living (ADL) functions. Results: In …all 279 AD patients (80.6 ± 7.2 years old, MMSE 20.0 ± 4.5), cognitive functions were well preserved until 12 months and even frontal assessment battery improved after 12 months although Hasegawa dementia scale-revised finally worsened at 24 months ( * p  <  0.05) with galantamine treatment. Affective and ADL functions were also well maintained after galantamine treatment with significant improvement of Geriatric Depression Scale scores at 3 months ( * p  <  0.05). Subanalyses showed the better response to galantamine for male and lower baseline function subgroups. Conclusions: Our present study (OGS) revealed a long-term efficacy of galantamine in very elderly AD patients, and suggested a better efficacy for male and baseline lower cognitive, affective, and ADL functions. Show more

Keywords: Activity of daily living, affective function, Alzheimer’s disease, cognitive function, dementia, galantamine

DOI: 10.3233/JAD-150308

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 609-617, 2015

Authors: Hessen, Erik | Nordlund, Arto | Stålhammar, Jacob | Eckerström, Marie | Bjerke, Maria | Eckerström, Carl | Göthlin, Mattias | Fladby, Tormod | Reinvang, Ivar | Wallin, Anders

Article Type: Research Article

Abstract: Background: There is a need to find very early markers for pre-clinical Alzheimer’s disease as interventions early in the disease process are thought to be most effective. Objective: The present study aimed to address the potential relation between cerebrospinal fluid (CSF) biomarkers and reduced cognitive function in a relatively young cohort of memory clinic patients with subjective cognitive decline. Methods: 122 patients (mean age 63 years) with subjective cognitive decline were recruited from two university memory clinics and followed for two years. Results: The main finding was that the …subgroup with objective memory decline during the study period had significantly higher T-tau at baseline than the group with improved memory. Baseline CSF variables showed a trend toward more pathological values in the patients with memory decline compared to those who improved or remained stable. The baseline memory score of those who declined was significantly better than the baseline score of those who improved over two years. The general trend for the whole group was improved memory and executive test scores. There were no differences in cognitive scores based on CSF quartiles at baseline, nor were there differences in cognitive outcome for patients with early amnestic mild cognitive impairment versus average cognitive function at baseline. Conclusions: The main finding that T-tau rather than amyloid-β was associated with memory decline do not support the prevailing opinion about the chain of events assumed to take place in Alzheimer’s disease. In addition, memory decline was not associated with poor baseline memory score. Thus, a memory cut-off indicating low baseline memory would not would have identified the declining group. Show more

Keywords: Cerebrospinal fluid biomarkers, early amnestic MCI, memory decline, mild cognitive impairment (MCI), pre-clinical AD, pre-clinical dementia, subjective cognitive decline, T-tau

DOI: 10.3233/JAD-150109

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 619-628, 2015

Authors: Virk, Sohaib A. | Eslick, Guy D.

Article Type: Research Article

Abstract: Background: Aluminum is the most studied environmental agent linked with Alzheimer’s disease (AD). However, it remains unclear whether levels are significantly elevated in AD sufferers. Objective: To systematically assess levels of aluminum in brain, serum, and cerebrospinal fluid (CSF) of AD cases and controls. Methods: Electronic searches of Medline, Embase, PubMed, and Cochrane Library were conducted up to June 2015. Studies reporting brain, serum, or CSF aluminum levels in individuals with AD and non-demented controls were included. Meta-analyses were performed using random-effects models and the pooled standardized mean difference (SMD) reported with …95% confidence intervals (CI). Results: Overall, 34 studies involving 1,208 participants and 613 AD cases met the criteria for inclusion. Aluminum was measured in brain tissue in 20 studies (n  = 386), serum in 12 studies (n  = 698), and CSF in 4 studies (n  = 124). Compared to control subjects, AD sufferers had significantly higher levels of brain (SMD 0.88; 95% CI, 0.25–1.51), serum (SMD 0.28; 95% CI, 0.03–0.54), and CSF (SMD 0.48; 95% CI, 0.03–0.93) aluminum. Sensitivity analyses excluding studies without age-matched controls did not impact upon these results. Conclusions: The findings of the present meta-analyses demonstrate that aluminum levels are significantly elevated in brain, serum, and CSF of patients with AD. These findings suggest that elevated aluminum levels, particularly in serum, may serve as an early marker of AD and/or play a role in the development of the disease. These results substantially clarify the existing evidence examining the link between chronic aluminum exposure and the development of AD. Show more

Keywords: Alzheimer disease, aluminum, meta-analysis, systematic review

DOI: 10.3233/JAD-150193

Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 629-638, 2015