Journal of Alzheimer's Disease - Volume 34, issue 4

Authors: Schröder, Nadja | Figueiredo, Luciana Silva | de Lima, Maria Noêmia Martins

Article Type: Review Article

Abstract: Over the last decades, studies from our laboratory and other groups using animal models have shown that iron overload, resulting in iron accumulation in the brain, produces significant cognitive deficits. Iron accumulation in the hippocampus and the basal ganglia has been related to impairments in spatial memory, aversive memory, and recognition memory in rodents. These results are corroborated by studies showing that the administration of iron chelators attenuates cognitive deficits in a variety of animal models of cognitive dysfunction, including aging and Alzheimer's disease models. Remarkably, recent human studies using magnetic resonance image techniques have also shown a consistent correlation …between cognitive dysfunction and iron deposition, mostly in the hippocampus, cortical areas, and basal ganglia. These findings may have relevant implications in the light of the knowledge that iron accumulates in brain regions of patients suffering from neurodegenerative diseases. A better understanding of the functional consequences of iron dysregulation in aging and neurological diseases may help to identify novel targets for treating memory problems that afflict a growing aging population. Show more

Keywords: Iron, memory, cognitive manifestations, neurodegenerative disorders, neonatal

DOI: 10.3233/JAD-121996

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 797-812, 2013

Authors: Kalbe, Elke | Calabrese, Pasquale | Fengler, Sophie | Kessler, Josef

Article Type: Review Article

Abstract: Many cognitive screening instruments have been developed during the last decades to detect mild cognitive dysfunction and dementia, and there is an ongoing discussion as to which tool should be used in which setting and which challenges have to be considered. Among other aspects, dependence on age is a recognized problem in screening tools which still has not found its way into common scoring procedures. Another aspect which has been handled very heterogeneously is which domain is represented in which proportion in the total score. Furthermore, screening ethnic minority patients has been identified as an important but so far widely …unresolved matter. In this review, four cognitive screening tools that all follow a common, stringent concept and pay regard to some critical aspects are described: the DemTect, a “generic” tool; the PANDA for Parkinson's disease patients; the EASY, a non-verbal, culture-fair screening test for patients with migration background; and the MUSIC for patients with multiple sclerosis. All of these screening instruments have an age-correction, provide a total score in which the different subtests are weighted according to their individual sensitivity and specificity, and include tasks that are specifically aligned to the cognitive profile of the target group, including the EASY with non-verbal, culture-fair tasks to overcome language and cultural barriers. The development, main characteristics, data, and limitations of these tools are presented and discussed against the background of the current landscape of cognitive screening tools. Show more

Keywords: Alzheimer's disease, cognition, cultural diversity, dementia, early diagnosis, mild cognitive impairment, multiple sclerosis, Parkinson's disease

DOI: 10.3233/JAD-122128

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 813-834, 2013

Authors: Izco, María | Pesini, Pedro | Pérez-Grijalba, Virginia | Fandos, Noelia | Sarasa, Manuel

Article Type: Short Communication

Abstract: Brain levels of amyloid-β (Aβ) are frequently assessed in transgenic mice models of Alzheimer's disease. The procedure involves tissue sample homogenization using different buffers in a sequential process. No attempt has been made to assess if these procedures are able to extract the total amount of Aβ present in the samples. Here we present data suggesting that standard protocols can lead to a dramatic underestimation of the Aβ content. Results show that higher extraction buffer volumes and at least two repetitions of the soluble and membrane-bound extraction steps are necessary for a more accurate estimation of the Aβ content in …brain tissues. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, animal models, ELISA, tissue extraction, tissue homogenization

DOI: 10.3233/JAD-121798

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 835-839, 2013

Authors: O'Bryant, Sid E. | Xiao, Guanghua | Edwards, Melissa | Devous, Michael | Gupta, Veer Bala | Martins, Ralph | Zhang, Fan | Barber, Robert | for the Texas Alzheimer's Research and Care Consortium (TARCC)

Article Type: Research Article

Abstract: Background: Mexican Americans are the fastest aging segment of the U.S. population, yet little scientific literature exists regarding the Alzheimer’s disease (AD) among this segment of the population. The extant literature suggests that biomarkers of AD will vary according to race/ethnicity though no prior work has explicitly studied this possibility. The aim of this study was to create a serum-based biomarker profile of AD among Mexican American. Methods: Data were analyzed from 363 Mexican American participants (49 AD and 314 normal controls) enrolled in the Texas Alzheimer’s Research & Care Consortium (TARCC). Non-fasting serum samples were analyzed using a …luminex-based multi-plex platform. A biomarker profile was generated using random forest analyses. Results: The biomarker profile of AD among Mexican Americans was different from prior work from non-Hispanic populations with regards to the variable importance plots. In fact, many of the top markers were related to metabolic factors (e.g., FABP, GLP-1, CD40, pancreatic polypeptide, insulin-like-growth factor, and insulin). The biomarker profile was a significant classifier of AD status yielding an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.77, 0.92, and 0.64, respectively. Combining biomarkers with clinical variables yielded a better balance of sensitivity and specificity. Conclusion: The biomarker profile for AD among Mexican American cases is significantly different from that previously identified among non-Hispanic cases from many large-scale studies. This is the first study to explicitly examine and provide support for blood-based biomarkers of AD among Mexican Americans. Areas for future research are highlighted. Show more

Keywords: Alzheimer's disease, biomarkers, Mexican American, neuropsychology

DOI: 10.3233/JAD-122074

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 841-849, 2013

Authors: Zahodne, Laura B. | Devanand, D.P. | Stern, Yaakov

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), cognition and function are only moderately correlated in cross-sectional studies, and studies of their longitudinal association are less common. One potential non-cognitive contributor to function is depression, which has been associated with poorer clinical outcomes. The current study investigated longitudinal associations between functional abilities, cognitive status, and depressive symptoms in AD. 517 patients diagnosed with probable AD and enrolled in The Multicenter Study of Predictors of Disease Course in Alzheimer's Disease were included. Patients were followed at 6-month intervals over 5.5 years. Longitudinal changes in the Blessed Dementia Rating Scale, modified Mini-Mental State Exam, and the …depression subscale of the Columbia University Scale for Psychopathology in AD were examined in a multivariate latent growth curve model that controlled for gender, age, education, and recruitment site. Results showed that cognition and function worsened over the study period, whereas depressive symptoms were largely stable. Rates of change in cognition and function were correlated across participants and coupled within participants, indicating that they travel together over time. Worse initial cognitive status was associated with faster subsequent functional decline, and vice versa. Higher level of depressive symptoms was associated with worse initial functioning and faster subsequent cognitive and functional decline. These findings highlight the importance of both cognitive and psychiatric assessment for functional prognosis. Targeting both cognitive and depressive symptoms in the clinical treatment of AD may have incremental benefit on functional abilities. Show more

Keywords: Activities of daily living, Alzheimer's disease, depression, statistical models

DOI: 10.3233/JAD-121921

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 851-860, 2013

Authors: Ellis, Kathryn A. | Lim, Yen Ying | Harrington, Karra | Ames, David | Bush, Ashley I. | Darby, David | Martins, Ralph N. | Masters, Colin L. | Rowe, Christopher C. | Savage, Greg | Szoeke, Cassandra | Villemagne, Victor L. | Maruff, Paul | the AIBL Research Group

Article Type: Research Article

Abstract: We aimed to characterize the nature and magnitude of cognitive decline in a group of healthy older adults with high and low levels of amyloid-β (Aβ) and who were APOE ε4 carriers and non-carriers. Healthy older adults underwent positron emission tomography neuroimaging for Aβ, APOE genotyping, and cognitive and clinical assessment as part of their baseline assessment in the Australian Imaging, Biomarker, and Lifestyle study. Cognitive function and clinical ratings were reassessed 18 months later. Linear mixed model analyses adjusted for baseline cognitive function indicated that relative to healthy older adults with low Aβ, healthy older adults with high Aβ …showed greater decline in episodic memory and language at 18 months. No decline on any measure of executive function, attention, or clinical rating was observed for healthy older adults with high Aβ levels. Compared to non-carriers, APOE ε4 carriers showed a greater decline only on the task of visual memory at the 18 month assessment. Importantly though, no interaction between APOE ε4 and Aβ was observed on any measure of cognitive function. The results of this study suggest that high Aβ load was associated with greater decline in episodic memory and language, that the magnitude of this decline was moderate and equivalent across both domains, and that APOE ε4 carriage did not moderate the relationship between Aβ and decline in memory and language functions. Show more

Keywords: Alzheimer's disease, amyloid-β, apolipoprotein E ε4, cognitive change, cognitive neuropsychology, healthy older adults

DOI: 10.3233/JAD-122170

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 861-871, 2013

Authors: Abbott, Ana C. | Calderon Toledo, Carla | Aranguiz, Florencia C. | Inestrosa, Nibaldo C. | Varela-Nallar, Lorena

Article Type: Research Article

Abstract: Tetrahydrohyperforin (IDN5706), a semi-synthetic derivative of hyperforin, has shown neuroprotective properties preventing the impairment of synaptic plasticity and cognitive decline in an in vivo model of Alzheimer's disease (AD). Considering the reported role of adult neurogenesis in the plasticity of the hippocampal network, we investigated whether IDN5706 affects adult neurogenesis and hippocampal function. In hippocampal progenitors cultured from adult rats, IDN5706 increased proliferation. Moreover, treatment with IDN5706 for 4 weeks increased cell proliferation in the subgranular zone (SGZ) of the hippocampus in 2 month-old wild-type mice in vivo. As determined by double labeling with BrdU and neuronal markers, IDN5706 treatment …increased the number of immature neurons and newborn mature neurons in the adult dentate gyrus. In addition, IDN5706 treatment improved long-term memory in a hippocampal-dependent spatial memory task. Finally, IDN5706 treatment increased cell proliferation and neural commitment in the SGZ of the double transgenic APPswe/PS1ΔE9 mouse model of AD. These results indicate that IDN5706 increases adult hippocampal neurogenesis and may have therapeutic value in neurological disorders in which adult neurogenesis is impaired. Show more

Keywords: Alzheimer's disease, hippocampus, long-term memory, neural progenitor cells, neurogenesis, tetrahydrohyperforin

DOI: 10.3233/JAD-121714

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 873-885, 2013

Authors: Balietti, Marta | Giorgetti, Belinda | Casoli, Tiziana | Solazzi, Moreno | Tamagnini, Francesco | Burattini, Costanza | Aicardi, Giorgio | Fattoretti, Patrizia

Article Type: Research Article

Abstract: Increasing experimental evidence indicates that synaptic alterations play a key role in cognitive decline in Alzheimer's disease (AD). Functional and structural synaptic changes progressively take place, beginning in the early phase of AD, mainly triggered by intracellular accumulation of soluble amyloid-β (Aβ) oligomers. These peptides also accumulate within mitochondria, heavily affecting their function and morphology, particularly in synaptic compartments. To better understand the role of mitochondrial impairment in synaptic alterations during the early stages of AD, a morphological investigation was performed by means of electron microscopy in the hippocampus of 3 month-old Tg2576 and transgene-negative littermate mice. In the stratum …moleculare of CA1 pyramidal cells (SMCA1) of transgenic animals compared to controls, we found significantly larger and less numerous synapses, with a significantly reduced fraction of the perforated subtype, as well as significantly smaller and more numerous mitochondria. In contrast, no differences between the two groups of mice were found in the inner molecular layer of the dentate gyrus. The reduction of synaptic contacts in SMCA1 indicates a precocious vulnerability of this region, and the synaptic enlargement may reflect a compensating process aimed at maintaining the overall contact density. Accordingly, mitochondrial modifications may represent a plastic reactive phenomenon aimed at sustaining the increased energy needs for synaptic remodeling, since mitochondrial morphology was perfectly preserved and smaller mitochondria are metabolically more efficient. Thus, morphological changes occurring at synaptic level in SMCA1 of 3 month-old Tg2576 mice might reflect a precocious vulnerability associated with a residual plastic reactivity which may slow down functional alterations. Show more

Keywords: Alzheimer's disease, hippocampus, mitochondria, synapses, synaptic plasticity, transgenic mice, ultrastructure

DOI: 10.3233/JAD-121711

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 887-896, 2013

Authors: Lachno, D. Richard | Evert, Barbara A. | Vanderstichele, Hugo | Robertson, Michael | DeMattos, Ronald B. | Konrad, Robert J. | Talbot, Jayne A. | Racke, Margaret M. | Dean, Robert A.

Article Type: Research Article

Abstract: The aim of this study was to validate new assays for measurement of amyloid-β (Aβ) peptides in cerebrospinal fluid (CSF) and plasma specimens in clinical studies of solanezumab according to current regulatory recommendations. Four assays based on the INNOTEST® β-AMYLOID(1-42) and prototype INNOTEST β-AMYLOID(1-40) kits were developed and validated. To render these assays ‘solanezumab-tolerant’, excess drug was added to calibrators, quality control, and test samples via a 2-fold dilution with kit diluent. Validation parameters were evaluated by repeated testing of human CSF and EDTA-plasma pools containing solanezumab. Calibration curve correlation coefficients for the four assays were ≥0.9985. …Intra- and inter-assay coefficients of variation for Aβ1-40 and Aβ1-42 were ≤13 and ≤15%, respectively for both matrices. Dilutional linearity, within and between assays, was demonstrated for both analytes in CSF and plasma at clinically relevant dilution factors. This dilution regimen was successfully applied during Phase 3 clinical sample analysis. Aβ1-40 and Aβ1-42 were stable in CSF and plasma containing solanezumab at 2–8°C and room temperature for up to 8 h and during 5 additional freeze-thaw cycles from ≤−20 and ≤−70°C. Results of parallel tests on stored clinical samples using INNOTEST methods and proprietary ELISA methods were closely correlated (r2 > 0.9), although bias in reported concentrations was observed between assays. In conclusion, the modified INNOTEST assays provided (relatively) accurate and precise quantification of Aβ1-40 and Aβ1-42 in CSF and plasma containing solanezumab according to established consensus validation criteria. The clinical experience with these assays post validation has shown them to be robust and reliable. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, assay validation, biomarker, cerebrospinal fluid, plasma, solanezumab

DOI: 10.3233/JAD-122317

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 897-910, 2013

Authors: Carmona, Pedro | Molina, Marina | Calero, Miguel | Bermejo-Pareja, Félix | Martínez-Martín, Pablo | Toledano, Adolfo

Article Type: Research Article

Abstract: In this study we have determined whether Raman and infrared spectroscopy of blood plasma differentiates Alzheimer's disease (AD) from normal aging of healthy controls. Spectroscopic analysis was conducted on blood plasma samples from 8 mild AD, 16 moderate AD, 11 severe AD, and 12 normal elderly control persons using Fourier transform spectrometers and a near-infrared laser beam as excitation source for Raman spectroscopy. Spectra were processed employing discriminant analysis to determine whether band areas and frequency-intensity relationships might reveal biochemical differences associated with AD. Seven spectral biomarkers were identified in the Raman regions of 1700–1600 cm−1 (protein secondary structure), …980–910 cm−1 (protein α-helices), 790–730 cm−1 (protein tertiary structure), and 440–390 cm−1 (protein backbone) and in the infrared regions of 1700–1600 cm−1 (protein secondary structure) and 1150–1000 cm−1 (oxidative stress). This discriminant analysis model differentiated AD from normal aging of elderly control persons with a sensitivity of 89% and specificity of 92%. Moreover, specificity increases to 100% for the detection of mild AD. In summary, our results open the possibility of using this spectroscopic approach as a non-invasive, rapid, and relatively inexpensive procedure for early accurate diagnosis of AD. Show more

Keywords: Alzheimer's disease, biomarker, diagnosis, infrared spectroscopy, Raman spectroscopy

DOI: 10.3233/JAD-122041

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 911-920, 2013