Journal of Alzheimer's Disease - Volume 37, issue 1

Authors: Sabbagh, Marwan N. | Perry, George | Hunsaker III, John C. | Schreurs, Bernard

Article Type: Obituary

DOI: 10.3233/JAD-131312

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 1-1, 2013

Authors: Di Francesco, Andrea | Arosio, Beatrice | Gussago, Cristina | Dainese, Enrico | Mari, Daniela | D'Addario, Claudio | Maccarrone, Mauro

Article Type: Short Communication

Abstract: Lipoxygenases play a major role in the neuropathology of Alzheimer's disease (AD), even though the underlying mechanisms are as yet poorly understood. Here, we studied the epigenetic regulation of 5-lipoxygenase (5-LOX) in peripheral blood mononuclear cells of subjects with late-onset AD and age-matched controls. We found a significant increase in 5-LOX gene expression in AD subjects compared to healthy controls, paralleled by increased 5-LOX protein and leukotriene B4 , the 5-LOX product. In addition, a consistent reduction in DNA methylation at 5-LOX gene promoter was documented in AD versus healthy subjects. Taken together, our findings further support a role for …5-LOX in vulnerability to neurodegeneration. Show more

Keywords: Alzheimer's disease, biomarker, DNA methylation, fatty acid amide hydrolase, 5-lipoxygenase, peripheral blood mononuclear cells

DOI: 10.3233/JAD-130506

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 3-8, 2013

Authors: Hou, Liming | Lee, Hyoung-gon | Han, Fang | Tedesco, Johnathan M. | Perry, George | Smith, Mark A. | Zagorski, Michael G.

Article Type: Research Article

Abstract: Oxidative stress and amyloid-β (Aβ) formation are important processes that occur in Alzheimer's disease (AD). Amyloid formation is associated with the aggregation and precipitation of the Aβ peptide, while oxidative stress results from an imbalance in pro-oxidant/antioxidant homeostasis that produces harmful reactive oxygen species. The methionine-35 (Met35) residue of the Aβ peptide plays an important role in AD oxidative stress events and the associated neurotoxicity. We and other research groups previously demonstrated that in vitro oxidation of the Met35 side-chain to the sulfoxide (Met35red → Met35ox ) impedes assembly and aggregation of monomeric Aβ peptide into protofibrils, the latter …being the immediate precursors of amyloid plaques. Here, we report that Met35 oxidation state affects the stability of preexisting amyloid fibrils and plaques, where the Met35red → Met35ox process leads to changes in the morphology of filaments, protofibrils, mature fibrils, and loss of Congo red birefringence in senile plaques isolated from the brains of AD patients. The most notable differences were in fibril flexibility, as evidenced by changes from straight fibrils to irregularly shaped, rope-like fibrils. These findings suggest that the Met35 oxidation state and amyloid plaque formation may be intimately linked. Show more

Keywords: Alzheimer's disease, amyloid-β, atomic force microscopy, fibrillization, oxidative stress

DOI: 10.3233/JAD-122389

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 9-18, 2013

Authors: Cui, Lili | Zhang, Yuan | Cao, Hao | Wang, Yan | Teng, Teng | Ma, Guoda | Li, You | Li, Keshen | Zhang, Yingjiu

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is neurodegenerative disease that occurs among the aging population and is associated with impaired cognitive function. Amyloid-β (Aβ) oligomers initiate the pathological cascade and represent a neuropathic hallmark of AD. Therefore, an approach that inhibits Aβ aggregation is an attractive therapeutic strategy for the treatment of AD. Ferulic acid (FA) is a phenolic compound that can inhibit Aβ42 fibril-induced cytotoxicity both in vitro and in vivo. However, few studies have demonstrated that FA interacts with Aβ42 oligomers. Here, we investigated whether FA inhibits Aβ42 oligomer-induced cytotoxicity and the effect of FA on Aβ aggregation. …Our results showed that FA reduced Aβ42 -induced neurotoxicity in SH-SY5Y cells. Moreover, using CD spectroscopy, we found that FA inhibited the formation of the β-sheets that are required for the Aβ42 monomer-to-oligomer transition but accelerated the Aβ42 oligomer-to-fibril transition. These phenomena were confirmed by transmission electron microscopy and thioflavin T fluorescence assay. The docking analysis between FA and Aβ42 monomer showed that FA may inhibit the aggregation of Aβ42 oligomers by blocking the hydrogen bond with the forming β-sheets. Taken together, we have identified a novel phenomenon in which FA inhibits the formation of Aβ42 oligomers while accelerating the transition of Aβ42 oligomers to fibrils, and we have shown that FA protects against Aβ42 -induced toxicity in vitro by preventing Aβ42 from forming oligomers. Show more

Keywords: Alzheimer's disease, amyloid-β, ferulic acid, oligomer

DOI: 10.3233/JAD-130164

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 19-28, 2013

Authors: Magnusson, Kristina | Sehlin, Dag | Syvänen, Stina | Svedberg, Marie M. | Philipson, Ola | Söderberg, Linda | Tegerstedt, Karin | Holmquist, Mats | Gellerfors, Pär | Tolmachev, Vladimir | Antoni, Gunnar | Lannfelt, Lars | Hall, Håkan | Nilsson, Lars N.G.

Article Type: Research Article

Abstract: Evidence suggests that amyloid-β (Aβ) protofibrils/oligomers are pathogenic agents in Alzheimer's disease (AD). Unfortunately, techniques enabling quantitative estimates of these species in patients or patient samples are still rather limited. Here we describe the in vitro and ex vivo characteristics of a new antibody-based radioactive ligand, [125 I]mAb158, which binds to Aβ protofibrils with high affinity. [125 I]mAb158 was specifically taken up in brain of transgenic mice expressing amyloid-β protein precursor (AβPP) as shown ex vivo. This was in contrast to [125 I]mAb-Ly128 which does not bind to Aβ. The uptake of intraperitoneally-administered [125 I]mAb158 into the brain was age- …and time-dependent, and saturable in AβPP transgenic mice with modest Aβ deposition. Brain uptake was also found in young AβPP transgenic mice that were devoid of Aβ deposits, suggesting that [125 I]mAb158 targets soluble Aβ protofibrils. The radioligand was diffusely located in the parenchyma, sometimes around senile plaques and only occasionally colocalized with cerebral amyloid angiopathy. A refined iodine-124-labeled version of mAb158 with much improved blood-brain barrier passage and a shorter plasma half-life might be useful for PET imaging of Aβ protofibrils. Show more

Keywords: Alzheimer's disease, amyloid-β protofibrils, antibody, brain uptake, positron emission tomography, transgenic mice

DOI: 10.3233/JAD-130029

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 29-40, 2013

Authors: Gordon, Brian A. | Blazey, Tyler | Benzinger, Tammie L. S. | Head, Denise

Article Type: Research Article

Abstract: The hippocampus is often treated as a uniform structure, but possesses differential projections to surrounding cortex along its longitudinal axis. This heterogeneity could create varied susceptibility to pathological influences, potentially leading to non-uniform volumetric associations with advancing age and Alzheimer's disease (AD). Previous examinations of aging and AD effects on hippocampal subdivisions have produced highly discrepant findings. To clarify these inconsistencies, we examined the hippocampal head, body, and tail in a large sample of 292 cognitively normal, 37 very mildly demented, and 18 mildly demented individuals, divided into two independent samples. As often done in the literature, we characterized qualitative …patterns across these regions, but extended these results by explicitly testing for quantitative differences. In each sample of cognitively normal individuals, the head and body demonstrated greater age effects than the tail. In each sample contrasting AD and cognitively normal individuals, all three regions showed significant volume reductions, with the greatest effect on the head. When examining increasing severity of dementia, the hippocampal head showed progressive volume loss, while the body and tail did not. The patterns of results examining both aging and AD were relatively consistent across the independent samples. These results indicate that there is an anterior-to-posterior gradient of loss within the hippocampus with both advancing age and AD. Show more

Keywords: Brain aging, dorsal hippocampus, long-axis, ventral hippocampus

DOI: 10.3233/JAD-130011

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 41-50, 2013

Authors: Gawinecka, Joanna | Nowak, Martin | Carimalo, Julie | Cardone, Franco | Asif, Abdul R. | Wemheuer, Wiebke M. | Schulz-Schaeffer, Walter J. | Pocchiari, Maurizio | Zerr, Inga

Article Type: Research Article

Abstract: Sporadic Creutzfeldt-Jakob disease (sCJD) is characterized by wide clinical and pathological variability, which is mainly influenced by the conformation of the misfolded prion protein (PrPSc ) and by methionine and valine polymorphism at codon 129 of the gene encoding PrP. This heterogeneity likely implies differences in the molecular cascades that lead to the development of certain disease phenotypes. Here, we investigated synaptic proteome patterns in two most common sCJD subtypes (MM1 and VV2) using 2D DIGE and mass spectrometry. We found that 23 distinct proteins were differentially expressed in at least one sCJD subtype when compared to age-matched controls. The …majority of these proteins displayed significant subtype-specific alterations, with only up-regulated glial fibrillary acidic protein and down-regulated spectrin alpha chain in both sCJD subtypes. Differentially expressed proteins found in this study are mainly involved in synaptic structure and activity, mitochondrial function, or calcium metabolism. Moreover, several of them have been already linked to the pathophysiological processes occurring in Alzheimer's disease. Show more

Keywords: Creutzfeldt-Jakob disease, 2D fluorescence difference gel electrophoresis (2D DIGE), proteomics, sCJD, synapse, synaptic dysfunction

DOI: 10.3233/JAD-130455

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 51-61, 2013

Authors: Kelly, Ronan J. | Minogue, Aedín M. | Lyons, Anthony | Jones, Raasay S. | Browne, Tara C. | Costello, Derek A. | Denieffe, Stephanie | O'Sullivan, Catherine | Connor, Thomas J. | Lynch, Marina A.

Article Type: Research Article

Abstract: Whereas the classical histological hallmarks of Alzheimer's disease (AD) are deposition of amyloid-containing plaques and development of neurofibrillary tangles, there is also clear evidence of inflammatory changes accompanied by the presence of activated microglia and astrocytosis. However, at this time, it remains uncertain whether inflammatory changes contribute to pathogenesis of the disease or if they are secondary to deposition of amyloid-β or other pathological changes. A greater understanding of the sequence of events would clearly improve development of strategies to delay progression of the disease. There is a realistic expectation that advances in imaging technology may provide the key to …uncovering this sequence. In this study, we employed non-invasive imaging techniques to examine changes in tissue state in hippocampus and cortex of transgenic mice which overexpress amyloid-β protein precursor and presenilin 1 and show that the observed increase in T1 relaxation time was associated with astrogliosis while the decrease in T2 relaxation time was associated with microglial activation. We explored the possibility that interferon-γ might trigger glial activation and demonstrate a genotype-related infiltration of macrophages and natural killer cells, which release interferon-γ. The evidence suggests that IFNγ triggers glial activation and expression of proinflammatory cytokines, and these changes, in turn, contribute to the decrease in long-term potentiation. Show more

Keywords: Glial activation, macrophages, natural killer (NK) cells, T1 and T2 relaxation times

DOI: 10.3233/JAD-130539

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 63-75, 2013

Authors: O'Hare, Eugene | Ardis, Tara | Page, Deaglan | Scopes, David I.C. | Kim, Eun-Mee

Article Type: Research Article

Abstract: The current study examined behavioral and histological effects of amyloid-β (Aβ) protein precursor (AβPP) overexpression in transgenic (Tg) rats created using the same gene, mutation, and promoter as the Tg2576 mouse model of Alzheimer's disease (AD). Male Tg+ rats were bred with female wild-type rats to generate litters of hemizygous Tg+ and Tg− offspring. Tg+ rats and Tg− littermates were tested for memory deficits at 4, 8, and 12 months old using a water-maze procedure. There were no significant behavioral differences between Tg+ rats and Tg− littermates at 4 months old but there …were significant differences at 8 and 12 months old, and in probe trials at 8 and 12 months old, the Tg+ rats spent significantly less time and covered less distance in the platform zone. Under acquisition of a fixed-consecutive number schedule at 3 months old, Tg− littermates demonstrated a longer latency to learning the response rule than Tg+ rats; while this might seem paradoxical, it is consistent with the role of overexpression of AβPP in learning. Histological analyses revealed activated astrocytes in brains of Tg+ rats but not Tg− littermates at 6 months old, and thioflavin-S positive staining in the hippocampus and cortex of 17-month old Tg+ rats but not Tg− littermates. Quantification of Aβ load in the brain at 22 months indicated high levels of Aβ38 , Aβ40 , and Aβ42 in the Tg+ rats. These data suggest this model might provide a valuable resource for AD research. Show more

Keywords: Amyloid-β protein precursor, animal model, behavior, histology, transgenic rat

DOI: 10.3233/JAD-130212

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 77-88, 2013

Authors: Royall, Donald R. | Palmer, Raymond F. | for the Texas Alzheimer's Research and Care Consortium

Article Type: Research Article

Abstract: We have constructed a latent dementia proxy, “δ”, and validated it in several datasets, including well characterized subjects participating in the Texas Alzheimer's Research and Care Consortium (TARCC) study. It may be possible to construct δ homologs from almost any ad hoc combination of cognitive and functional status measures. δ homologs may also be relatively immune to measurement error, including cultural, linguistic, or educational biases. These properties make factor scores derived from latent variables a potentially attractive solution for dementia case-finding in rural or minority populations. Here we have explored an alternative and briefer assessment by which to construct a …δ homolog and validate the resulting latent variable (dMA) in Mexican-American (MA) TARCC subjects. dMA, composed of simple “bedside” dementia screening instruments, achieves Areas Under the Receiver Operative Curve that rival those of δ itself. Ethnicity has a small effect on dMA's performance. These results suggest that it may be possible to validly export dMA into other MA populations, or to export δ homolog factor scores from one population to another. Show more

Keywords: Aging, cognition, dementia, functional status, g

DOI: 10.3233/JAD-130353

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 89-97, 2013

Authors: Perri, Roberta | Fadda, Lucia | Caltagirone, Carlo | Carlesimo, Giovanni Augusto

Article Type: Research Article

Abstract: Background: Different roles have been attributed to mesio-temporal areas and frontal lobes in declarative memory functioning, and qualitative differences have been observed in the amnesic symptoms due to pathological damage of these two portions of the central nervous system. Objective: The aim of the present study was to look for memory profiles related to pathological involvement in the temporal and frontal structures in patients with different dementia syndromes on word-list and prose memory tasks. Methods: 20 patients with Alzheimer’s disease (AD), 20 with frontal variant of FTD (fvFTD), 20 with subcortical ischemic vascular dementia (SIVD), and …20 with Lewy body dementia (LBD) and 34 healthy subjects (NCs) were submitted to word-list and prose memory tasks. Results: All groups performed similarly on both the immediate and delayed recall of the word-list. Conversely, AD patients performed worse than all the other dementia groups on the immediate prose recall. On delayed prose recall, AD patients performed worse than fvFTD and SIVD patients but similar to LBD patients. Differential scores between word-list and prose tests were minimal in the AD group and very pronounced in fvFTD and SIVD groups. Conclusion: The combined use of the prose and word-list tasks evidenced a “mesio-temporal” memory profile in AD patients as opposed to a “frontal” one in fvFTD and SIVD patients and a mixed profile in the LBD patients. In particular, a differential score between the two tests can be useful in differentiating AD patients from patients with other forms of dementia. Show more

Keywords: Alzheimer's disease, frontotemporal dementia, Lewy body dementia, memory recall, subcortical ischemic vascular disease

DOI: 10.3233/JAD-130347

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 99-107, 2013

Authors: Lo, Adrian C. | Iscru, Emilia | Blum, David | Tesseur, Ina | Callaerts-Vegh, Zsuzsanna | Buée, Luc | De Strooper, Bart | Balschun, Detlef | D'Hooge, Rudi

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a consequence of degenerative brain pathology with amyloid plaque deposition and neurofibrillary tangle formation. These distinct aspects of AD neuropathology have been suggested to induce a cascade of pathological events ultimately leading to neurodegeneration as well as cognitive and behavioral decline. Amyloid and tau neuropathology is known to develop along distinct stages and affect parts of the brain differentially. In this study, we examined two mouse AD lines (AβPPPS1-21 and Tau22 mice), which mimic different partial aspects of AD pathology, at comparable stages of their pathology. Since prefrontal cortex (PFC) is one of the first regions …to be affected in clinical AD, we compared long-term potentiation (LTP) of synaptic responses in medial PFC of AβPPPS1-21 and Tau22 mice. Frontal LTP was impaired in AβPPPS1-21 mice, but not in Tau22 mice. Consequently, we observed different behavioral defects between AβPPPS1-21 and Tau22 animals. Apart from spatial learning deficits, AβPPPS1-21 transgenic mice were impaired in fear learning, aversion learning, and extinction learning, whereas THY-Tau22 were impaired in appetitive responding. Discriminant function analysis identified critical behavioral variables that differentiated AβPPPS1-21 and THY-Tau22 mice from wild type littermates, and further confirmed that amyloid- versus tau-pathology differentially affects brain function. Show more

Keywords: Alzheimer's disease, amyloid, cognition, prefrontal cortex, synaptic plasticity, tau

DOI: 10.3233/JAD-122296

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 109-125, 2013

Authors: Raven, Erika P. | Lu, Po H. | Tishler, Todd A. | Heydari, Panthea | Bartzokis, George

Article Type: Research Article

Abstract: Background: Iron can catalyze damaging free radical reactions. With age, iron accumulates in brain gray matter regions and may contribute to the risk of developing age-related diseases such as Alzheimer’s disease (AD). Prior MRI studies demonstrated increased iron deposits in basal ganglia regions; however, the hippocampus (Hipp), which is heavily damaged in AD, and comparator regions that are resistant to AD damage, such as thalamus (Th), have rarely been examined. Objective: To assess iron levels and evidence of tissue damage in Hipp and Th of AD subjects and healthy controls. Methods: Thirty-one AD and sixty-eight healthy …control subjects participated in this study. High- and low-field strength MRI instruments were used in combination to quantify iron content of ferritin molecules (ferritin iron) using the field dependent relaxation rate increase (FDRI) method. Decreased transverse relaxation rate (R2 ) was used as an index of tissue damage. Results: Compared with healthy controls, AD subjects had increased ferritin iron in Hipp (p = 0.019) but not Th (p = 0.637), and significantly decreased R2 in Hipp (p < 0.001) but not Th (p = 0.37). In the entire sample, FDRI and R2 were negatively correlated. Conclusion: The data shows that in AD, Hipp damage occurs in conjunction with ferritin iron accumulation. Prospective studies are needed to evaluate how increasing iron levels may influence the trajectory of tissue damage and cognitive and pathologic manifestations of AD. Show more

Keywords: Alzheimer's disease, chelation, dementia, ferritin, field dependent relaxation rate increase (FDRI), iron, magnetic resonance imagining (MRI), myelin, prevention, treatment

DOI: 10.3233/JAD-130209

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 127-136, 2013

Authors: Mez, Jesse | Cosentino, Stephanie | Brickman, Adam M. | Huey, Edward D. | Mayeux, Richard

Article Type: Research Article

Abstract: The study's objective was to compare demographics, APOE genotypes, and rate of rise over time in functional impairment in neuropsychologically defined language, typical, and memory subgroups of clinical Alzheimer's disease (AD). 1,368 participants from the National Alzheimer's Coordinating Center database with a diagnosis of probable AD (CDR 0.5–1.0) were included. A language subgroup (n = 229) was defined as having language performance >1 SD worse than memory performance. A memory subgroup (n = 213) was defined as having memory performance >1 SD worse than language performance. A typical subgroup (n = 926) was defined as having a difference in language …and memory performance of <1 SD. Compared with the memory subgroup, the language subgroup was 3.7 years older and more frequently self-identified as African American (OR = 3.69). Under a dominant genetic model, the language subgroup had smaller odds of carrying at least one APOEε4 allele relative to the memory subgroup. While this difference was present for all ages, it was more striking at a younger age (OR = 0.19 for youngest tertile; OR = 0.52 for oldest tertile). Compared with the memory subgroup, the language subgroup rose 35% faster on the Functional Assessment Questionnaire and 44% faster on CDR sum of boxes over time. Among a subset of participants who underwent autopsy (n = 98), the language, memory, and typical subgroups were equally likely to have an AD pathologic diagnosis, suggesting that variation in non-AD pathologies across subtypes did not lead to the observed differences. The study demonstrates that a language subgroup of AD has different demographics, genetic profile, and disease course in addition to cognitive phenotype. Show more

Keywords: African Americans, age of onset, Alzheimer's disease, aphasia, apolipoprotein E4, focal onset Alzheimer's disease, demographic factors, language, longitudinal studies, memory

DOI: 10.3233/JAD-130320

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 137-146, 2013

Authors: Annweiler, Cedric | Montero-Odasso, Manuel | Llewellyn, David J. | Richard-Devantoy, Stéphane | Duque, Gustavo | Beauchet, Olivier

Article Type: Research Article

Abstract: Background: Hypovitaminosis D is associated with global cognitive impairment in adults. It remains unclear which domain-specific cognitive functions are affected with hypovitaminosis D. Objective. To systematically review and quantitatively synthesize the association of serum 25-hydroxyvitamin D (25OHD) concentrations with episodic memory and executive functions in adults. Methods: A Medline and PsycINFO® libraries search was conducted on May 2012, with no limit of date, using the Medical Subject Headings (MeSH) terms “Vitamin D” OR “Hydroxycholecalciferols” combined with the MeSH terms “Memory” OR “Memory Disorders” OR “Executive Function” OR “Attention” OR “Cognition” OR “Cognition disorders” OR “Dementia” OR “Alzheimer …disease” OR “Neuropsychological Tests”. Fixed-effects meta-analysis was performed from 12 eligible studies using an inverse-variance method. Results: Of the 285 selected studies, 14 observational studies (including 3 prospective cohort studies) and 3 interventional studies met the selection criteria. All were of good quality. The number of participants ranged from 44–5,692 community-dwellers (0–100% women). In the pooled analysis, although episodic memory disorders showed only modest association with lower 25OHD concentrations (summary effect size of the difference (ES) = −0.09 [95%CI:−0.16;−0.03]), associations of greater magnitude were found with executive dysfunctions (processing speed: mean difference of Trail Making Test (TMT)-A score = 4.0 [95%CI:1.20;6.83]; mental shifting: mean difference of TMT-B score = 12.47 [95%CI:6.78;18.16]; information updating tests: ES = −0.31 [95%CI:−0.5;−0.09]). The pooled risk of incident decline of TMT-B score was OR = 1.25 [95%CI:1.05;1.48] in case of initial lower 25OHD concentrations. Vitamin D repletion resulted in improved executive functions (ES = −0.50 [95%CI:−0.69;−0.32] for before-and-after comparison), but exhibited no difference with control groups (ES = 0.14 [95%CI:−0.04;0.32] for between-group comparison after intervention). Conclusion: Lower serum 25OHD concentrations predict executive dysfunctions, especially on mental shifting, information updating and processing speed. The association with episodic memory remains uncertain. Show more

Keywords: Aging, cognition, episodic memory, executive functions, meta-analysis, neuroendocrinology, vitamin D

DOI: 10.3233/JAD-130452

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 147-171, 2013

Authors: Ito, Kaori | Corrigan, Brian | Romero, Klaus | Anziano, Richard | Neville, Jon | Stephenson, Diane | Lalonde, Richard

Article Type: Research Article

Abstract: Background: The placebo response and the underlying disease progression is difficult to differentiate in longitudinal Alzheimer’s disease (AD) studies, yet it is crucial to understand for designing clinical trials and interpreting results. Objectives: The placebo response in ADAS-cog11 from various studies was evaluated against model predictions derived from historical placebo data to demonstrate potential interpretation of study results using a prior understanding of expected disease progression. Methods: The placebo response component from a previously published disease progression model was used to estimate the longitudinal placebo response, and the disease progression in the placebo group in …various case studies were evaluated. In addition, placebo data from the Coalition Against Major Diseases (CAMD) database in mild to moderate AD patients is described. Results: The case studies demonstrated potential different results in disease progression in a placebo group, and the impact on understanding the magnitude of drug effect. Baseline cognitive function is an important covariate of disease progression, therefore, it is important to evaluate the baseline severity and predict disease progression accordingly when comparing trial results. Furthermore, study duration, sample size, and study design may affect the placebo response, all of which have the potential to confound understanding of study results. Conclusion: The recent failures in Phase III AD studies are not likely due to insufficient cognitive decline in the control groups. A meta-analytic approach using all available data provides a robust understanding of placebo effect, disease progression, and potential interpretation of treatment effects, and offers a useful tool to aid in both trial design and interpretation. Show more

Keywords: ADAS-cog, Alzheimer's disease, Coalition Against Major Diseases (CAMD), disease progression, meta-analysis, placebo response

DOI: 10.3233/JAD-130575

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 173-183, 2013

Authors: Gezen-Ak, Duygu | Dursun, Erdinç | Hanağası, Haşmet | Bilgiç, Başar | Lohman, Ebba | Araz, Ömür Selin | Atasoy, İrem L. | Alaylıoğlu, Merve | Önal, Burak | Gürvit, Hakan | Yılmazer, Selma

Article Type: Research Article

Abstract: Identifying early-detection biomarkers have become an increasingly important approach in the treatment and prevention of Alzheimer's disease (AD). In this study, we investigated the potential of brain-derived neurotrophic factor (BDNF), complement factor H (CFH), tumor necrosis factor-α (TNFα), interleukin 10 (IL-10), and heat shock protein 90 (Hsp90) as serum biomarkers for AD in a cohort of the Turkish population because they have been suggested to be associated with AD. Serum BDNF, CFH, TNFα, IL-10, and Hsp90 levels in three groups of patients, early-onset AD (EOAD; age of onset < 65; n = 22), late-onset AD (LOAD; age of onset > …65; n = 54), and mild cognitive impairment (MCI) (n = 30), were compared with age-matched healthy controls (age < 65, n = 18 and age > 65; n = 32) using ELISA. The serum BDNF levels significantly decreased and TNFα levels significantly increased in the EOAD and LOAD groups compared to the age-matched healthy controls. There was a correlation between serum TNFα and IL-10 levels in the LOAD and healthy control groups. Serum CFH levels in the LOAD and MCI patients were significantly decreased compared with controls. Serum Hsp90 levels in the EOAD, LOAD, and MCI patients were significantly decreased compared with controls. The protein misfolding, the inflammatory response, and decreased neurotrophic factor synthesis are all suggested to be related to AD type brain pathology, and our results indicate these alterations might be traced from serum samples. For accurate early diagnosis of AD, it is important to determine a profile of alterations in multiple biomarkers in large-scale population studies. Show more

Keywords: Alzheimer's disease, brain-derived neurotrophic factor (BDNF), complement factor H (CFH), ELISA, heat shock protein 90 (Hsp90), interleukin 10 (IL-10), mild cognitive impairment (MCI), tumor necrosis factor-α (TNFα)

DOI: 10.3233/JAD-130497

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 185-195, 2013

Authors: Smith, J. Carson | Nielson, Kristy A. | Antuono, Piero | Lyons, Jeri-Annette | Hanson, Ryan J. | Butts, Alissa M. | Hantke, Nathan C. | Verber, Matthew D.

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) is associated with early memory loss, Alzheimer's disease (AD) neuropathology, inefficient or ineffective neural processing, and increased risk for AD. Unfortunately, treatments aimed at improving clinical symptoms or markers of brain function generally have been of limited value. Physical exercise is often recommended for people diagnosed with MCI, primarily because of its widely reported cognitive benefits in healthy older adults. However, it is unknown if exercise actually benefits brain function during memory retrieval in MCI. Here, we examined the effects of exercise training on semantic memory activation during functional magnetic resonance imaging (fMRI). Seventeen MCI participants …and 18 cognitively intact controls, similar in sex, age, education, genetic risk, and medication use, volunteered for a 12-week exercise intervention consisting of supervised treadmill walking at a moderate intensity. Both MCI and control participants significantly increased their cardiorespiratory fitness by approximately 10% on a treadmill exercise test. Before and after the exercise intervention, participants completed an fMRI famous name discrimination task and a neuropsychological battery, Performance on Trial 1 of a list-learning task significantly improved in the MCI participants. Eleven brain regions activated during the semantic memory task showed a significant decrease in activation intensity following the intervention that was similar between groups (p-values ranged 0.048 to 0.0001). These findings suggest exercise may improve neural efficiency during semantic memory retrieval in MCI and cognitively intact older adults, and may lead to improvement in cognitive function. Clinical trials are needed to determine if exercise is effective to delay conversion to AD. Show more

Keywords: Alzheimer's disease, dementia, exercise, magnetic resonance imaging, memory, non-pharmacologic treatment, physical activity, physical fitness

DOI: 10.3233/JAD-130467

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 197-215, 2013

Authors: Natunen, Teemu | Parrado, Antonio R. | Helisalmi, Seppo | Pursiheimo, Juha-Pekka | Sarajärvi, Timo | Mäkinen, Petra | Kurkinen, Kaisa M.A. | Mullin, Kristina | Alafuzoff, Irina | Haapasalo, Annakaisa | Bertram, Lars | Soininen, Hilkka | Tanzi, Rudolph E. | Hiltunen, Mikko

Article Type: Research Article

Abstract: Golgi-localized γ-ear-containing ADP-ribosylation factor-binding protein (GGA3) is a central regulator of trafficking and degradation of BACE1 (β-site AβPP-cleaving enzyme), the rate-limiting enzyme in the production of amyloid-β (Aβ) in Alzheimer's disease (AD). Here, we assessed the potential role of GGA3 in AD pathogenesis using independent neuropathological, case-control, and family-based human sample cohorts. Increased BACE1 levels coincided with decreased GGA3 levels and with elevated phosphorylation status of eIF2α-Ser51 in the temporal cortex of AD patients as compared to age-matched controls. Severity of the disease did not alter mRNA or protein levels of GGA3 in the inferior temporal cortex of AD patients, …while a positive correlation between GGA3 and the levels of total, but not phosphorylated, tau was observed. Genetically, we did not observe consistent evidence for association between AD risk and common GGA3 polymorphisms across a number of independent sample cohorts. However, a nominally significant association was observed with rs2242230 (p < 0.05) among the Finnish case-control cohort. Accordingly, mRNA and protein levels of GGA3 in the inferior temporal cortex of AD patients did not significantly correlate with rs2242230 genotype status. While the present study indicates that GGA3 is involved in the cellular processes relevant for AD pathogenesis, the genetic data do not support the idea that common GGA3 polymorphisms would contribute to AD risk. Show more

Keywords: Alzheimer's disease, amyloid-β, β-secretase, Braak staging, eukaryotic translation initiation factor 2α, frozen brain tissue samples, Golgi-localized γ-ear-containing ADP-ribosylation factor-binding protein, polymorphism, protein stability, tau protein

DOI: 10.3233/JAD-130104

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 217-232, 2013

Authors: Wiesmann, Maximilian | Jansen, Diane | Zerbi, Valerio | Broersen, Laus M. | Garthe, Alexander | Kiliaan, Amanda J.

Article Type: Research Article

Abstract: There is accumulating evidence showing that lifestyle factors like diet may influence the onset and progression of Alzheimer's disease (AD). Our previous studies suggest that a multi-nutrient diet, Fortasyn, containing nutritional precursors and cofactors for membrane synthesis, viz. docosahexaenoic acid, eicosapentaenoic acid, uridine-mono-phosphate, choline, phospholipids, folic acid, vitamins B6, B12, C, E, and selenium, has an ameliorating effect on cognitive deficits in an AD mouse model. In the present study we analyzed learning strategies and memory of 11-month-old AβPPswe/PS1dE9 (AβPP/PS1) mice in the Morris water maze (MWM) task performed after nine months of dietary intervention with a control diet or …a Fortasyn diet to characterize diet-induced changes in cognitive performance. The Fortasyn diet had no significant effect on MWM task acquisition. To assess hippocampus-dependent learning, the strategies that the mice used to find the hidden platform in the MWM were analyzed using the swim path data. During the fourth day of the MWM, AβPP/PS1 mice on control diet more often used the non-spatial random search strategy, while on the Fortasyn diet, the transgenic animals exhibited more chaining strategy than their wild-type littermates. During the probe trial, AβPP/PS1 mice displayed no clear preference for the target quadrant. Notably, in both transgenic and nontransgenic mice on Fortasyn diet, the latency to reach the former platform position was decreased compared to mice on the control diet. In conclusion, this specific nutrient combination showed a tendency to improve searching behavior in AβPP/PS1 mice by increasing the use of a more efficient search strategy and improving their swim efficiency by decreasing the latency to reach the former platform position. Show more

Keywords: Alzheimer's disease, cognition, docosahexaenoic acids, learning, memory, transgenic mice

DOI: 10.3233/JAD-130179

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 233-245, 2013

Article Type: Other

DOI: 10.3233/JAD-130180

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 247-249, 2013