Journal of Alzheimer's Disease - Volume 35, issue 3

Authors: Singh, Ajay | Haldar, Swati | Horback, Katharine | Tom, Cynthia | Zhou, Lan | Meyerson, Howard | Singh, Neena

Article Type: Research Article

Abstract: Prion protein (PrPC ) is implicated in the pathogenesis of prion disorders, but its normal function is unclear. We demonstrate that PrPC is a ferrireductase (FR), and its absence causes systemic iron deficiency in PrP knock-out mice (PrP-/- ). When exposed to non-transferrin-bound (NTB) radioactive-iron (59 FeCl3 ) by gastric-gavage, PrP-/- mice absorb significantly more 59 Fe from the intestinal lumen relative to controls, indicating appropriate systemic response to the iron deficiency. Chronic exposure to excess dietary iron corrects this deficiency, but unlike wild-type (PrP+/+ ) controls that remain iron over-loaded, PrP-/- mice revert back to the …iron deficient phenotype after 5 months of chase on normal diet. Bone marrow (BM) preparations of PrP-/- mice on normal diet show relatively less stainable iron, and this phenotype is only partially corrected by intraperitoneal administration of excess iron-dextran. Cultured PrP-/- BM-macrophages incorporate significantly less NTB-59 Fe in the absence or presence of excess extracellular iron, indicating reduced uptake and/or storage of available iron in the absence of PrPC . When expressed in neuroblastoma cells, PrPC exhibits NAD(P)H-dependent cell-surface and intracellular FR activity that requires the copper-binding octa-peptide-repeat region and linkage to the plasma membrane for optimal function. Incorporation of NTB-59 Fe by neuroblastoma cells correlates with FR activity of PrPC , implicating PrPC in cellular iron uptake and metabolism. These observations explain the correlation between PrPC expression and cellular iron levels, and the cause of iron imbalance in sporadic-Creutzfeldt-Jakob-disease brains where PrPC accumulates as insoluble aggregates. Show more

Keywords: Brain, ferrireductase, iron, neurotoxicity, prion, sporadic Creutzfeldt-Jakob disease

DOI: 10.3233/JAD-130218

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 541-552, 2013

Authors: Nissou, Marie-France | Brocard, Jacques | El Atifi, Michèle | Guttin, Audrey | Andrieux, Annie | Berger, François | Issartel, Jean-Paul | Wion, Didier

Article Type: Research Article

Abstract: Seasonal or chronic vitamin D deficiency and/or insufficiency is highly prevalent in the human population. Receptors for 1,25-dihydroxyvitamin D3, the hormonal metabolite of vitamin D, are found throughout the brain. To provide further information on the role of this hormone on brain function, we analyzed the transcriptomic profiles of mixed neuron-glial cell cultures in response to 1,25-dihydroxyvitamin D3. 1,25-dihydroxyvitamin D3 treatment increases the mRNA levels of 27 genes by at least 1.9 fold. Among them, 17 genes were related to neurodegenerative and psychiatric diseases, or brain morphogenesis. Notably, 10 of these genes encode proteins potentially limiting the progression of Alzheimer's …disease. These data provide support for a role of 1,25-dihydroxyvitamin D3 in brain disease prevention. The possible consequences of circannual or chronic vitamin D insufficiencies on a tissue with a low regenerative potential such as the brain should be considered. Show more

Keywords: Alzheimer's disease, neurodegenerative diseases, Parkinson's disease, psychiatric diseases, vitamin D

DOI: 10.3233/JAD-122005

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 553-564, 2013

Authors: Imfeld, Patrick | Brauchli Pernus, Yolanda B. | Jick, Susan S. | Meier, Christoph R.

Article Type: Research Article

Abstract: Epidemiologic studies on age-specific incidence rates (IRs) separating Alzheimer's disease (AD) and vascular dementia (VaD) in the UK are scarce. We sought to assess IRs of AD and VaD in the UK and to compare co-morbidities and medication use between patients with AD, VaD, or without dementia. We identified cases aged ≥65 years with an incident diagnosis of AD or VaD between 1998 and 2008 using the General Practice Research Database (GPRD). We assessed IRs, stratified by age and gender, matched one dementia-free control patient to each demented patient, and analyzed co-morbidities and medication use. We identified 7,086 AD and …4,438 VaD cases. Overall, the IR of AD was 1.59/1,000 person-years (py) (95% CI 1.55–1.62) and the IR of VaD 0.99/1,000 py (95% CI 0.96–1.02). For AD, IRs were higher for women than for men, but not for VaD. Except for orthostatic hypotension, the prevalence of all cardiovascular (CV) co-morbidities and exposure to CV drugs was lower in patients with AD than in corresponding controls, whereas the opposite was true for VaD. The lower prevalence of CV diseases in patients with AD may be a true finding or the result of a channeling effect, i.e., the possibility that demented patients with CV diseases may be more likely diagnosed with VaD than AD. Show more

Keywords: Alzheimer's disease, comorbidity, dementia, epidemiology, vascular

DOI: 10.3233/JAD-121819

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 565-573, 2013

Authors: Thurm, Franka | Antonenko, Daria | Schlee, Winfried | Kolassa, Stephan | Elbert, Thomas | Kolassa, Iris-Tatjana

Article Type: Research Article

Abstract: Performance monitoring tasks are suitable for investigating aging-related decline in executive functions. However, little is known about performance monitoring in premature pathological aging and mild cognitive impairment (MCI). This study recorded the error-related negativity (ERN) and the correct-related negativity (CRN) as indices of performance monitoring and compared these responses in older adults with MCI to the ones of younger and older adult controls. No differences in either ERN or CRN were found between younger and older adult controls. Compared to both control groups, we observed a more negatively pronounced CRN in MCI subjects. Only in this group did the amplitude …of the CRN not differ from the one of the ERN. In general, larger differences between both components (i.e., ERN > CRN) were associated with better performances in cognitive tests requiring inhibition and executive control. These results indicate that electrophysiological correlates of performance monitoring (ERN and CRN) are differentially affected by aging and MCI. Show more

Keywords: Aging, EEG, event-related potentials, executive function, mild cognitive impairment, neuropsychological test

DOI: 10.3233/JAD-121348

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 575-587, 2013

Authors: Navarro, Ana | del Valle, Eva | Mártínez, Eva | Ordóñez, Cristina | Pérez, Cristina | Tolivia, Jorge

Article Type: Research Article

Abstract: A highly selective, rapid, inexpensive, simple, and immunocytochemical compatible fluorescence staining method for Alzheimer's disease hallmark lesions applicable to sections of human specimens embedded in paraffin is described. Human necropsy material was fixed in buffered formalin, sectioned at 10 μm, mounted on slides, deparaffinized, and partially hydrated (70% ethanol). After partial hydration, sections were stained for 10 min in a solution of 0.2% Congo red in 70% isopropanol. After washing in 70% isopropanol and rehydration, auto-fluorescence of sections were quenched (optional) and processed for immunocytochemistry (optional). Finally, sections were mounted in an adequate mounting medium. Amyloid deposits appear pink at …light microscopy and all Alzheimer's disease hallmark lesions appear orange or red under fluorescence microscopy using blue or green exciting light, respectively. The present method can be used in combination with all pre- or post-immunocytochemical techniques. Show more

Keywords: Aging, amyloidosis, apolipoprotein D, fluorescence microscopy, immunocytochemistry, neuropathology

DOI: 10.3233/JAD-122386

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 589-597, 2013

Authors: Scheff, Stephen W. | Price, Douglas A. | Schmitt, Frederick A. | Roberts, Kelly N. | Ikonomovic, Milos D. | Mufson, Elliott J.

Article Type: Research Article

Abstract: Amnestic mild cognitive impairment (aMCI) is considered to be one of the early stages in the progression from no cognitive impairment (NCI) to Alzheimer's disease (AD). Individuals with aMCI have increased levels of AD-type neuropathology in multiple regions of the neocortex and hippocampus and demonstrate a loss of synaptic connectivity. Recent neuroimaging studies have reported increased levels of 11 C-PiB (Pittsburgh, compound B) in regions of the neocortex including the precuneus region of the medial parietal lobe. This cortical region has been implicated in episodic memory, which is disrupted early in the progression of AD. In this study, unbiased stereology …coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the precuneus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI did not reveal a statistically significant decline in total synapses compared to the NCI cohort while the AD group did show a modest but significant decline. Synaptic numbers failed to correlate with several different cognitive tasks including the Mini-Mental State Examination scores and episodic memory scores. Although levels of [3 H]PiB binding were elevated in both the aMCI and AD groups, it did not strongly correlate with synaptic counts. These results support the idea that despite increased amyloid load, the precuneus region does not show early changes in synaptic decline during the progression of AD. Show more

Keywords: Alzheimer's disease, early onset, episodic memory, synapses, synaptic plasticity

DOI: 10.3233/JAD-122353

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 599-609, 2013

Authors: Roed, Line | Grave, Gisle | Lindahl, Torbjørn | Rian, Edith | Horndalsveen, Peter O. | Lannfelt, Lars | Nilsson, Christer | Swenson, Frank | Lönneborg, Anders | Sharma, Praveen | Sjögren, Magnus

Article Type: Research Article

Abstract: Background: The focus on Alzheimer’s disease (AD) is shifting from dementia to the prodromal stage of the disorder, to a large extent due to increasing efforts in trying to develop disease modifying treatment for the disorder. For development of disease-modifying drugs, a reliable and accurate test for identification of mild cognitive impairment (MCI) due to AD is essential. Objective: In the present study, MCI progressing to AD will be predicted using blood-based gene expression. Material and Methods: Gene expression analysis using qPCR was performed on blood RNA from a cohort of patients with amnestic MCI (aMCI; …n = 66). Within the aMCI cohort, patients progressing to AD within 1 to 2 years were grouped as MCI converters (n = 34) and the patients remaining at the MCI stage after 2 years were grouped as stable MCI (n = 32). AD and control populations were also included in the study. Results: Multivariate statistical method partial least square regression was used to develop predictive models which later were tested using leave-one-out cross validation. Gene expression signatures that identified aMCI subjects that progressed to AD within 2 years with a prediction accuracy of 74%–77% were identified for the complete dataset and subsets thereof. Conclusion: The present pilot study demonstrates for the first time that MCI that evolves into AD dementia within 2 years may be predicted by analyzing gene expression in blood. Further studies will be needed to validate this gene signature as a potential test for AD in the predementia stage. Show more

Keywords: Alzheimer's disease, biomarkers, diagnostic tests, gene expression signatures, mild cognitive impairment

DOI: 10.3233/JAD-122404

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 611-621, 2013

Authors: Carvalho, Cristina | Machado, Nuno | Mota, Paula C. | Correia, Sónia C. | Cardoso, Susana | Santos, Renato X. | Santos, Maria S. | Oliveira, Catarina R. | Moreira, Paula I.

Article Type: Research Article

Abstract: Type 2 diabetes (T2D) is considered a major risk factor for Alzheimer's disease (AD). To elucidate the links between both pathological conditions, we compared behavioral and cognitive functions, cerebral amyloid-β peptide (Aβ) levels and vasculature integrity of 11-month-old T2D and AD mice. For this purpose, we performed behavioral tests (open field, object recognition, Y-maze, and elevated plus maze tests), ELISA to assess plasma markers of endothelial/vascular dysfunction, spectrophotometric assays to evaluate cerebral vascular permeability and enzymatic activities, and immunohistochemistry for the assessment of Aβ levels. Both T2D and AD showed similar behavioral and cognitive anomalies characterized by increased fear and …anxiety and decreased learning and memory abilities. Interestingly, both groups of animals presented increased plasma markers of endothelial/vascular dysfunction and permeability of cerebral vasculature and impaired mitochondrial enzymatic activities. In addition, a significant increase in Aβ levels was observed in the cortex and hippocampus of T2D mice. These results support the notion that T2D predisposes to cerebrovascular alterations, cognitive decline, and development of AD. Show more

Keywords: Alzheimer's disease, brain vasculature, behavior and cognitive function, mitochondria, type 2 diabetes

DOI: 10.3233/JAD-130005

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 623-635, 2013

Authors: Perry, George | Rodrigues, Roberto | Castellani, Rudy J.

Article Type: Book Review

DOI: 10.3233/JAD-130090

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 637-637, 2013

Article Type: Other

DOI: 10.3233/JAD-130006

Citation: Journal of Alzheimer's Disease, vol. 35, no. 3, pp. 639-641, 2013