Journal of Alzheimer's Disease - Volume 42, issue 2

Authors: Desai, Gauri S. | Zheng, Chen | Geetha, Thangiah | Mathews, Suresh T. | White, B. Douglas | Huggins, Kevin W. | Zizza, Claire A. | Broderick, Tom L. | Babu, Jeganathan Ramesh

Article Type: Review Article

Abstract: Epidemiological and observational studies indicate a positive correlation between type 2 diabetes (T2DM) and dementia, with an increased risk of dementia and Alzheimer's disease (AD) associated with insulin-treated diabetes patients. The purpose of this review is to reveal the molecular mechanisms that connect physiological and pathological processes commonly observed in T2DM and AD. Conformational modifications in peptide residues, such as amyloid-β peptide in AD and amylin in T2DM have been shown to instigate formation of insoluble protein aggregates that get deposited in extracellular spaces of brain and pancreatic tissue thus disrupting their normal function. Impaired insulin signaling plays a critical …role in AD pathogenesis by reducing IRS-associated PI3 kinase activity and increasing GSK-3β activity. GSK-3β has been suggested to be a component of the γ-secretase complex and is involved in amyloid-β protein precursor processing. GSK-3β along with CDK5 is responsible for hyperphosphorylation of tau leading to the formation of neurofibrillary tangles. In summary, there is evidence to believe that a molecular link connects AD and T2DM and has potential for further investigation toward development of an effective therapeutic target. Show more

Keywords: Alzheimer's disease, amyloid-β, insulin receptor, neurofibrillary tangle, type 2 diabetes

DOI: 10.3233/JAD-140018

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 347-356, 2014

Authors: Farías, Gonzalo A. | Guzmán-Martínez, Leonardo | Delgado, Carolina | Maccioni, Ricardo B.

Article Type: Review Article

Abstract: Alzheimer's disease is a growing health problem worldwide. The pharmaceutical industry has not recently developed any new drugs that have had a significant impact on the natural history of the disease, so considerable attention has been given to nutraceuticals and nutritional bioactive compounds that can be obtained directly from diet or supplementation. These compounds may be able to modify physiopathological processes responsible for neurodegeneration and/or to have pro-cognitive properties. Here, we review current knowledge on the role of diet modifications, lipid and carbohydrates consumption, vitamin supplementation, and the possible effects of antioxidant and nutraceutical compounds with neuroprotective activity, in the …prevention and treatment of Alzheimer's disease and related disorders. Show more

Keywords: Alzheimer's disease, antioxidants, clinical trials, food supplements, nutraceuticals, vitamins

DOI: 10.3233/JAD-132741

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 357-367, 2014

Authors: Femminella, Grazia Daniela | Rengo, Giuseppe | Komici, Klara | Iacotucci, Paola | Petraglia, Laura | Pagano, Gennaro | de Lucia, Claudio | Canonico, Vincenzo | Bonaduce, Domenico | Leosco, Dario | Ferrara, Nicola

Article Type: Review Article

Abstract: Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimer's disease are also implicated in autonomic nervous system regulation, and it has been hypothesized that the deficit in central cholinergic function observed in Alzheimer's disease could likely lead to autonomic dysfunction. Several feasible tests can be used in clinical practice for the assessment of parasympathetic and sympathetic functions, especially in terms of cardiovascular autonomic modulation. In this review, we describe the different tests available and the evidence from the literature which …indicate a definite presence of autonomic dysfunction in dementia at various degrees. Importantly, the recognition of dysautonomia, besides possibly being an early marker of dementia, would help prevent the disabling complications which increase the risk of morbidity, institutionalization, and mortality in these individuals. Show more

Keywords: Alzheimer's disease, autonomic nervous system, baroreflex, functional recovery, orthostatic hypotension

DOI: 10.3233/JAD-140513

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 369-377, 2014

Authors: Macdonald, Ian R. | Rockwood, Kenneth | Martin, Earl | Darvesh, Sultan

Article Type: Short Communication

Abstract: Cholinesterase inhibitors are the standard of care for Alzheimer's disease (AD). Acetylcholinesterase (AChE) catalyzes the hydrolysis of the cholinergic neurotransmitter acetylcholine. However, the related enzyme butyrylcholinesterase (BuChE) also breaks down acetylcholine and is likewise targeted by the same clinical cholinesterase inhibitors. The lack of clinical efficacy for the highly specific and potent AChE inhibitor, (−) huperzine A, is intriguing, given the known cholinergic deficit in AD. Based on the proven efficacy of inhibitors affecting both cholinesterases and the apparent failure of specific AChE inhibition, focused BuChE inhibition seems important for more effective treatment of AD. Therefore, BuChE-selective inhibitors provide promise …for improved benefit. Show more

Keywords: Acetylcholinesterase, bisnorcymserine, butyrylcholinesterase, donepezil, (−) huperzine A, rivastigmine

DOI: 10.3233/JAD-140219

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 379-384, 2014

Authors: Ishibashi, Kenji | Miura, Yoshiharu | Oda, Keiichi | Ishiwata, Kiichi | Ishii, Kenji

Article Type: Short Communication

Abstract: Increased plasma glucose levels can cause the regional reduction of fluorine-18-labeled fluorodeoxyglucose (18 F-FDG) uptake in the posterior cingulate, precuneus, and/or temporoparietal cortices as an Alzheimer's disease (AD)-like pattern. However, the association of such an AD-like pattern of cerebral 18 F-FDG uptake with AD pathophysiology is unknown. We report a case of a 70-year-old patient with mild cognitive impairment, and show that the AD-like pattern of cerebral 18 F-FDG uptake during a hyperglycemic state could be reversible and is not associated with amyloid-β accumulation. Our case concludes that the AD-like pattern is dependent on the plasma glucose level and independent …of AD pathophysiology. Show more

Keywords: 11C-PiB, 18F-FDG, hyperglycemia, PET

DOI: 10.3233/JAD-140639

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 385-389, 2014

Authors: Oldmeadow, Christopher | Holliday, Elizabeth G. | McEvoy, Mark | Scott, Rodney | Kwok, John B.J. | Mather, Karen | Sachdev, Perminder | Schofield, Peter | Attia, John

Article Type: Short Communication

Abstract: There are a growing number of large cohorts of older persons with genome-wide genotyping data available, but APOE is not included in any of the common microarray platforms. We compared directly measured APOE genotypes with those imputed using microarray data and the “1000 Genomes” dataset in a sample of 320 Caucasians. We find 90% agreement for ε2/ε3/ε4 genotypes and 93% agreement for predicting ε4 status, yielding kappa values of 0.81 and 0.84, respectively. More stringent thresholds around allele number estimates can increase this agreement to 90–97% and kappas of 0.90–0.93.

Keywords: Agreement, APOE, concordance, dementia, genotyping

DOI: 10.3233/JAD-140846

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 391-393, 2014

Authors: Stockburger, Carola | Gold, Vicki A.M. | Pallas, Thea | Kolesova, Natalie | Miano, Davide | Leuner, Kristina | Müller, Walter E.

Article Type: Research Article

Abstract: Recent data suggest that the combined effect of oxidative stress due to aging and slightly elevated amyloid-β (Aβ) levels initiate Alzheimer's disease (AD) long before the clinical onset. Investigations of this early phase are hampered by the lack of cellular or animal models reflecting this scenario. We used SH-SY5Y cells stably transfected with an additional copy of the human AβPP gene and artificial aging by complex I inhibition. These cells show slightly elevated Aβ levels, moderately decreased ATP levels, impaired mitochondrial membrane potential, and decreased mitochondrial respiration. Assessing mitochondrial dynamics with three different methods reveals a distinct shift toward mitochondrial …fission and fragmentation in SH-SY5Y AβPPwt cells. We also performed electron cryo-tomography of isolated mitochondria to reveal that there were no major differences between SH-SY5Y control and SH-SY5Y AβPPwt mitochondria with respect to swelling or loss of cristae. Dystrophic neurites are an early pathological feature of AD. Interestingly, SH-SY5Y AβPPwt cells exhibit significantly longer neurites, likely due to substantially elevated levels of sAβPPα. Complex I inhibition also shows substantial effects on mitochondrial dynamics, impairs neuritogenesis, and elevates Aβ levels in both cell types. In SH-SY5Y AβPPwt cells, these defects were more pronounced due to a relatively elevated Aβ and a reduced sAβPPα production. Our findings suggest that the progression from low Aβ levels to the beginning of AD takes place in the presence of oxidative stress during normal aging. This mechanism not only results from additive effects of both mechanisms on mitochondrial function but might also be additionally aggravated by altered amyloidogenic processing. Show more

Keywords: Aging, Alzheimer's disease, amyloid-β, mitochondrial dynamics, mitochondrial function

DOI: 10.3233/JAD-140381

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 395-411, 2014

Authors: Saint-Aubert, Laure | Sagot, Catherine | Wallon, David | Hannequin, Didier | Payoux, Pierre | Nemmi, Federico | Bezy, Catherine | Chauveau, Nicolas | Campion, Dominique | Puel, Michèle | Chollet, François | Pariente, Jérémie

Article Type: Research Article

Abstract: We report the case of a 65-year-old woman, clinically diagnosed with the logopenic variant of primary progressive aphasia (PPA), and carrier of C9ORF72 expansion, despite cerebrospinal fluid biomarkers suggesting Alzheimer's disease (AD). She underwent structural MRI, metabolic PET, and amyloid PET imaging using florbetapir. Comparison with healthy controls revealed widespread hypometabolism, left sided cortical atrophy, and an increased cortical amyloid load. No difference in amyloid binding was found between the patient and predemential AD patients. This case provides evidence of amyloidopathy in a carrier of C9ORF72 expansion exhibiting a clinical profile of the logopenic variant of PPA.

Keywords: Alzheimer's disease, C9ORF72 expansion, florbetapir, logopenic primary aphasia

DOI: 10.3233/JAD-140222

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 413-420, 2014

Authors: Kim, Eosu | Jung, Young-Sang | Kim, Hyunjeong | Kim, Jin-Sup | Park, Minsun | Jeong, Jihyeon | Lee, Su Kyoung | Yoon, Ho-Geun | Hwang, Geum-Sook | Namkoong, Kee

Article Type: Research Article

Abstract: Discovery of biomarkers in peripheral blood is a crucial step toward the early diagnosis and repetitive monitoring of treatment response for Alzheimer's disease (AD). Metabolomics is a promising technology that can identify unbiased biomarkers. To explore potential blood biomarkers for AD via metabolic profiling with high-resolution magic angle spinning nuclear magnetic resonance techniques, we identified changes in peripheral blood metabolomic profiles in response to amyloid-β (Aβ)-induced neuroinflammation and co-treatment with gallate, a phytochemical known to have anti-neuroinflammatory properties. Alzheimer's-like (AL) model mice were produced by intracerebroventricular infusion of Aβ and compared with normal control mice with infusion of vehicle. AL …mice were treated with either gallate (treated AL mice) or vehicle (untreated AL mice). Metabolomic analyses of both whole blood and plasma showed a clear separation between untreated AL mice and the other two groups, with levels of several metabolites involved in energy metabolism, including pyruvate and creatine, being significantly reduced in untreated AL mice compared with control and treated AL mice. Gallate treatment suppressed Aβ-induced overproduction of the inflammatory cytokine tumor necrosis factor-α in the hippocampus and normalized plasma levels of the affected metabolites. These results suggest that plasma levels of several metabolites could be indicative of both brain pathology and therapeutic responses, supporting the possibility of a close relationship between central neuroinflammation and systemic metabolic disturbance. These findings also suggest the potential of NMR-based metabolomics as a method to identify novel plasma biomarkers for AD, which could be confirmed by future translational research with human patients. Show more

Keywords: Alzheimer's disease, biomarker, creatine, metabolomics, neuroinflammation, NMR, plasma, pyruvate

DOI: 10.3233/JAD-132165

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 421-433, 2014

Authors: Conway, Megan | Nafar, Firoozeh | Straka, Tatjana | Mearow, Karen

Article Type: Research Article

Abstract: Upregulation of heat shock proteins, such as Hsp70 and HspB1/Hsp27, have been associated with an amelioration of the deficits in animal models of Alzheimer's disease (AD). HspB1 is reported to be increased in AD brains and to accumulate in plaques, but whether this localization is an attempt by HspB1 to ameliorate the detrimental effects of amyloid-β (Aβ) on cells or part of the disease process is unknown. Here we explore the potential effects of the HspB1 on amyloid-β protein precursor (AβPP) processing and distribution within HEK293 stable cell lines expressing either AβPPwt or AβPPsw. We compare AβPP production, distribution, and …release of proteolytic products (including Aβ40 and Aβ42 ) to determine possible modifications in the presence of HspB1. We also investigate whether HspB1 interacts with Aβ or its precursor, AβPP, and whether, through this interaction, it is able to alter AβPP processing or release of Aβ peptide. Coexpression of HspB1 resulted in increased cellular holoAβPP as well as C-terminal fragments. Further, expression of HspB1 attenuated the release of Aβ42 from the AβPPsw cells. In summary, we have shown that expression of HspB1 alters AβPP expression and processing in cell lines expressing AβPPwt and AβPPsw. Furthermore, the presence of HspB1 decreased the amount of Aβ42 released by the cell lines. Thus in addition to its effects on protecting cells from the potentially toxic effects of Aβ, HspB1 also appears to be involved in modulating cellular levels of AβPP, although an understanding of the underlying mechanisms requires further investigation. Show more

Keywords: AβPPwt, AβPPsw, cell line, protein expression, small heat shock protein

DOI: 10.3233/JAD-140348

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 435-450, 2014

Authors: Eichler, Tilly | Thyrian, Jochen René | Hertel, Johannes | Köhler, Leonore | Wucherer, Diana | Dreier, Adina | Michalowsky, Bernhard | Teipel, Stefan | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Primary data about rates of formal diagnosis of dementia in the German primary care sector are widely lacking. Objectives: Main objectives are to analyze the rate of syndrome diagnosis in primary care patients who screened positive for dementia, the distribution of differential diagnoses, and factors associated with undiagnosed dementia. Methods: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is an ongoing general practitioner (GP)-based, randomized, controlled intervention trial. A total of 4,064 patients (≥70 years, living at home) recruited from 108 participating GP practices were screened for dementia (DemTect < 9). Of 692 eligible …patients (17%), a total of 406 subjects (59%) provided informed consent. Present analyses are based on the data of 243 patients with complete baseline assessment on January 1, 2014 (preliminary data). Formal diagnoses were retrieved from the medical records of the treating GPs. A conditional fixed effect regression analysis was performed to analyze factors associated with undiagnosed dementia. Results: A total of 40% of patients who screened positive for dementia had been formally diagnosed with dementia. Unspecified dementia was diagnosed in 53%, vascular dementia in 24%, and Alzheimer’s disease in 19% of these patients. Undiagnosed dementia was significantly associated with a higher mean score in the Mini-Mental State Examination (odds ratio, 1.11; p < 0.01, 95% confidence interval 1.04–1.18). Conclusions: The diagnosis rate of dementia in German primary care (40%) is well within the range of the international data (20–50%). The results emphasize the need for action to enhance recognition and differential diagnosis of dementia. Show more

Keywords: Dementia, differential diagnosis, early diagnosis, primary health care, screening

DOI: 10.3233/JAD-140354

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 451-458, 2014

Authors: Nguyen, Thuy-Vi V. | Shen, Lin | Vander Griend, Lilith | Quach, Lisa N. | Belichenko, Nadia P. | Saw, Nay | Yang, Tao | Shamloo, Mehrdad | Wyss-Coray, Tony | Massa, Stephen M. | Longo, Frank M.

Article Type: Research Article

Abstract: The p75 neurotrophin receptor (p75NTR ) is involved in degenerative mechanisms related to Alzheimer's disease (AD). In addition, p75NTR levels are increased in AD and the receptor is expressed by neurons that are particularly vulnerable in the disease. Therefore, modulating p75NTR function may be a significant disease-modifying treatment approach. Prior studies indicated that the non-peptide, small molecule p75NTR ligands LM11A-31, and chemically unrelated LM11A-24, could block amyloid-β-induced deleterious signaling and neurodegeneration in vitro, and LM11A-31 was found to mitigate neuritic degeneration and behavioral deficits in a mouse model of AD. In this study, we determined whether these …in vivo findings represent class effects of p75NTR ligands by examining LM11A-24 effects. In addition, the range of compound effects was further examined by evaluating tau pathology and neuroinflammation. Following oral administration, both ligands reached brain concentrations known to provide neuroprotection in vitro. Compound induction of p75NTR cleavage provided evidence for CNS target engagement. LM11A-31 and LM11A-24 reduced excessive phosphorylation of tau, and LM11A-31 also inhibited its aberrant folding. Both ligands decreased activation of microglia, while LM11A-31 attenuated reactive astrocytes. Along with decreased inflammatory responses, both ligands reduced cholinergic neurite degeneration. In addition to the amelioration of neuropathology in AD model mice, LM11A-31, but not LM11A-24, prevented impairments in water maze performance, while both ligands prevented deficits in fear conditioning. These findings support a role for p75NTR ligands in preventing fundamental tau-related pathologic mechanisms in AD, and further validate the development of these small molecules as a new class of therapeutic compounds. Show more

Keywords: Alzheimer's disease, LM11A-31, LM11A-24, p75 neurotrophin receptor

DOI: 10.3233/JAD-140036

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 459-483, 2014

Authors: Shinagawa, Shunichiro | Nakajima, Shinichiro | Plitman, Eric | Graff-Guerrero, Ariel | Mimura, Masaru | Nakayama, Kazuhiko | Miller, Bruce L.

Article Type: Research Article

Abstract: Frontotemporal dementia (FTD) is a neurodegenerative disorder, associated with a progressive decline in behavior caused by focal degeneration of the frontal lobes. Psychosis was an underestimated symptom of FTD, however, recent genetic research has revealed a high prevalence of psychosis in certain genetic groups. The primary objective of this work is to review the literature on psychosis in FTD and to propose directions for future research, with reference to findings on psychosis in schizophrenia. A search was performed using PubMed, MEDLINE, and EMBASE. Search terms included “frontotemporal dementia”, “psychosis”, “schizophreni* ”, “psychotic symptoms”, “hallucinations”, and “delusions”, and it identified 122 …articles. Results revealed: 1) prevalence is approximately 10%, 2) TDP-43 type B and FUS pathologies might have relatively high frequency of psychosis, 3) psychosis in FTD is higher with genetic mutations of C9ORF72 and GRN, 4) imaging researches did not achieve conclusive results, and 5) no treatment for psychosis in FTD is currently available. A limitation of this systematic review is that it includes a small number of studies specifically examining psychosis in FTD. It is suggested that a possible overlap exists between FTD and schizophrenia. This potential overlap indicates a vulnerability to psychosis due to brain systems and pathways shared by these disorders. Show more

Keywords: Frontotemporal dementia, gene mutation, neuropathology, psychosis, schizophrenia

DOI: 10.3233/JAD-140312

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 485-499, 2014

Authors: Oosterveld, Saskia M. | Kessels, Roy P.C. | Hamel, Renske | Ramakers, Inez H.G.B. | Aalten, Pauline | Verhey, Frans R.J. | Sistermans, Nicole | Smits, Lieke L. | Pijnenburg, Yolande A. | van der Flier, Wiesje M. | Olde Rikkert, Marcel G.M. | Melis, René J.F.

Article Type: Research Article

Abstract: Co-morbidity and frailty are common in Alzheimer's disease (AD) and may contribute to the heterogeneity in clinical manifestations of the disease. We cross-sectionally investigated whether co-morbidity and frailty were independently associated with the clinical manifestation of AD in the 4C–Dementia study; a multicenter, longitudinal study in newly diagnosed AD patients. Clinical manifestation was operationalized using a composite of cognitive performance (neuropsychological assessment), activities of daily living (Disability Assessment for Dementia; DAD) and neuropsychiatric symptoms (Neuropsychiatric Inventory). As predictors of prime interest, co-morbidity was determined using the Cumulative Illness Rating Scale (CIRS-G) and frailty by the Fried criteria. In total, 213 …AD patients participated (mean age 75 ± 10 years; 58% females). In linear regression models adjusted for age, gender, education, and disease duration, CIRS-G (β = −0.21, p < 0.01) and frailty (β = −0.34, p < 0.001) were separately associated with clinical AD manifestation. However, CIRS-G (β = −0.12, p = 0.12) lost statistical significance when both were combined (frailty: β = −0.31, p < 0.001). Models with the individual components of clinical AD manifestation as dependent variables show significant associations between cognitive performance and CIRS-G (β = −0.22, p = 0.01), and between DAD and frailty (β = −0.37, p < 0.001). Our findings indicate that physical health and clinical AD manifestation are associated. This association may be responsible for part of the heterogeneity in the presentation of AD. This emphasizes the importance of adequate assessment of co-morbid medical conditions and frailty in patients with AD. Show more

Keywords: Activities of daily living, Alzheimer's disease, co-morbidity, cognitive performance, dementia, frailty

DOI: 10.3233/JAD-140138

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 501-509, 2014

Authors: Tian, Li | Zhang, Ke | Tian, Zhi-Ying | Wang, Tao | Shang, De-Shu | Li, Bo | Liu, Dong-Xin | Fang, Wen-Gang | Wang, Zhan-You | Chen, Yu-Hua

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative dementia characterized by pathological senile plaques composed of amyloid-β (Aβ) in the cerebral cortex and hippocampus. Bone marrow-derived monocytes of patients with AD migrate across the blood-brain barrier into the brain, but are defective at clearing Aβ in the neuritic plaques. However, the underlying mechanisms remain unclear. Here, in patients with AD, we found that cathepsin D, a major lysosomal aspartic protease, was underexpressed in monocytes, resulting in the defective degradation of Aβ by monocytes/macrophages. Further, downregulation of cathepsin D in THP-1 cells significantly reduced the clearance of amyloid plaques in the brain …sections of AβPP/PS1 mice. The clearance ability was recovered by the overexpression of cathepsin D in AD monocytes. These results suggest that decreased expression of cathepsin D in the peripheral monocytes is a potential signature of AD, and that this decreased expression is involved in Aβ degradation and AD pathogenesis. Show more

Keywords: Alzheimer's disease, amyloid-β, cathepsin D, monocyte

DOI: 10.3233/JAD-132192

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 511-520, 2014

Authors: Trujillo-Estrada, Laura | Dávila, José Carlos | Sánchez-Mejias, Elisabeth | Sánchez-Varo, Raquel | Gomez-Arboledas, Angela | Vizuete, Marisa | Vitorica, Javier | Gutiérrez, Antonia

Article Type: Research Article

Abstract: The progressive cognitive decline leading to dementia in Alzheimer's disease (AD) patients is the consequence of a severe loss of synapses and neurons affecting particular cell subpopulations in selected brain areas, with the subiculum being one of the earliest regions displaying severe atrophy and pathology. The lack of significant neuronal loss in most AD models is, in fact, the major shortcoming for the preclinical evaluation of drugs that could have greater potential in patients to alleviate or prevent this disease. In this study, using immunohistochemical and stereological approaches, we have analyzed the histopathological events in the subiculum of AβPP751SwedLondon/PS1M146L mice, …a transgenic model that displays neuronal vulnerability at early ages in hippocampus and entorhinal cortex. Our results indicate that the subiculum is the earliest affected region in the hippocampus, showing a selective early loss of both principal neurons (28%) and SOM-positive interneurons (69%). In addition, our data demonstrate the existence of an early axonal and synaptic pathology, which may represent the beginning of the synaptic disruption and loss. These neurodegenerative processes occur in parallel, and closely related, with the onset and accelerated progression of the extracellular amyloid-β deposition, thus suggesting plaques as major contributors of neuronal/axonal damage. Data reported here indicate that this AD model displays a selective AD-like neurodegenerative phenotype in highly vulnerable regions, including the subiculum, and therefore can be a very useful model for testing the therapeutic ability of potential compounds to protect neurons and ameliorate disease symptoms. Show more

Keywords: Alzheimer's disease, amyloid-β plaques, axonal damage, hippocampus, neuronal loss, subiculum, transgenic mice

DOI: 10.3233/JAD-140495

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 521-541, 2014

Authors: Sun, Lin | Guo, Chunni | Wang, Tao | Li, Xia | Li, Guanjun | Luo, Yanli | Xiao, Shifu

Article Type: Research Article

Abstract: Bone morphogenetic protein 6 (BMP6) has neuroprotective effects against various neuronal injuries, but its effect on amyloid-β (Aβ)-induced neurotoxicity remains unclear. We exposed rat hippocampal neurons to different concentrations of Aβ25-35 to induce neurotoxicity, and then treated cells with BMP6 to assess the neuroprotective effects. In vivo, we bilaterally injected Aβ1-40 into basal forebrain to simulate the neuropathological process of Alzheimer's disease (AD), and explored changes in the expression of BMP6 and LIMK1. Our data demonstrated that BMP6 prevented apoptosis induced by a high dose of Aβ25-35 , and inhibited rod formation induced by low dose of Aβ25-35 …in hippocampal neurons. Forebrain injection of Aβ1-40 led to a significant downregulation of BMP6, and inactivation of LIMK1 pathway in basal forebrain, whereas the opposite changes were observed in hippocampus. Our results suggest that BMP6 has neuroprotective effects against Aβ25-35 . The BMP6 and LIMK1 pathways may have different expression patterns at different stages of AD, and be self-regulating via a negative feedback mechanism between different brain regions. Show more

Keywords: actin, Alzheimer's disease, amyloid-β, bone morphogenetic protein, rod

DOI: 10.3233/JAD-140231

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 543-554, 2014

Authors: Qiu, Wei Qiao | Au, Rhoda | Zhu, Haihao | Wallack, Max | Liebson, Elizabeth | Li, Huajie | Rosenzweig, James | Mwamburi, Mkaya | Stern, Robert A.

Article Type: Research Article

Abstract: Our recent study reported that amylin, a pancreatic peptide that readily crosses the blood-brain barrier, improves learning and memory in Alzheimer's disease mouse models. However, the relationship between peripheral amylin and cognition in humans is unknown. In this follow-up study, using a cross-sectional, homebound elderly population, improvement in cognitive function with increasing quartiles of plasma amylin was suggested by positive association with verbal memory (p = 0.0002) and visuoconstruction tasks (p = 0.004), and inverse association with timed measures of attention (p < 0.0001) and executive function (p = 0.04). After adjusting for demographic information, apolipoprotein E4 allele, diabetes, stroke, …kidney function, and lipid profile, log10 of plasma amylin remained associated with these cognitive domains. In contrast, plasma amyloid-β peptide was not associated with these specific cognitive domains. Our study suggests that peripheral amylin may be protective for cognitive decline, especially in the domains affected by Alzheimer's disease. Show more

Keywords: Amylin, cognition, memory, visuospatial and executive function

DOI: 10.3233/JAD-140210

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 555-563, 2014

Authors: Ma, Ling-Li | Yu, Jin-Tai | Wang, Hui-Fu | Meng, Xiang-Fei | Tan, Chen-Chen | Wang, Chong | Tan, Lan

Article Type: Research Article

Abstract: This study examined the association between cancer and Alzheimer's disease (AD) by a quantitative meta-analysis of cohort studies. Studies were identified by searching PubMed database through 1966 to December 2013 using the terms “Alzheimer's disease”, “neoplasm”, and “cancer”. Six studies met the inclusion criteria in the overall meta-analysis. We pooled effect sizes using fixed-effects and random-effects models. Furthermore, we also tested for heterogeneity and publication bias. The results suggested that individuals diagnosed with AD had a decreased risk for incident cancer by 42% (95% CI, 0.40–0.86; p < 0.05), and patients with a history of cancer had a 37% decreased …risk of AD (RR = 0.63; 95% CI, 0.56–0.72; p = 0.495). The Egger's test for publication bias (p = 0.280) showed no significant evidence for bias in the data from studies on AD and cancer risk. In summary, our meta-analysis demonstrated an inverse association between cancer and AD. Show more

Keywords: Alzheimer's disease, cancer, meta-analysis, neoplasm

DOI: 10.3233/JAD-140168

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 565-573, 2014

Authors: Imtiaz, Bushra | Tuppurainen, Marjo | Tiihonen, Miia | Kivipelto, Miia | Soininen, Hilkka | Hartikainen, Sirpa | Tolppanen, Anna-Maija

Article Type: Research Article

Abstract: Background: Association between oophorectomy and/or hysterectomy and dementia in context of hormone therapy (HT) use is ambiguous. Objective: To assess whether oophorectomy, hysterectomy, and hysterectomy with bilateral oophorectomy are related to risk of Alzheimer’s disease (AD), whether the possible indication for surgery plays a role, and if the associations are modified by HT. Methods: Our nationwide register based case–control (1 : 1) study included all women with clinically-verified AD diagnoses, residing in Finland on December 31, 2005 (n of cases = 19,043, n of controls = 19,043). AD cases, diagnosed according to NINCS-ADRDA and the DSM-IV …criteria, were identified from Special Reimbursement Register. Information on HT use was collected from national prescription register, and data on surgery and uterine/ovarian/cervical cancer were obtained from the hospital discharge register. Most of the women (91.8%) were over 51 years of age when the surgery was performed. Results: Oophorectomy, hysterectomy, and hysterectomy with bilateral oophorectomy were associated with lower risk of AD (OR/95% CI: 0.85/0.75–0.97, 0.89/0.81–0.97 and 0.85/0.75–0.98, respectively) among women without the history of uterine/ovarian/cervical cancer, although the absolute risk difference was small. The association was not evident in women with uterine/ovarian/cervical cancer history (3.00/0.20–44.87 for all surgeries). The associations were not modified by HT use, which was independently associated with AD risk, with longer use showing protective association. Conclusion: Our findings indicate that oophorectomy with or without hysterectomy after commencement of natural menopause is not an important determinant of AD risk in older age and support the critical window hypothesis for HT use. Show more

Keywords: Alzheimer's disease, cognition, dementia, estrogen, hormone therapy, hysterectomy, menopause, oophorectomy, radical hysterectomy

DOI: 10.3233/JAD-140336

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 575-581, 2014

Authors: Hogervorst, Eef

Article Type: Article Commentary

DOI: 10.3233/JAD-140909

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 583-586, 2014

Authors: Kawahara, Kohichi | Suenobu, Michita | Ohtsuka, Hideyuki | Kuniyasu, Akihiko | Sugimoto, Yukihiko | Nakagomi, Madoka | Fukasawa, Hiroshi | Shudo, Koichi | Nakayama, Hitoshi

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative process involving amyloid-β (Aβ) peptide deposition, neuroinflammation, and progressive memory loss. Here, we evaluated whether oral administration of retinoic acid receptor (RAR)α,β agonist Am80 (tamibarotene) or specific retinoid X receptor (RXR) pan agonist HX630 or their combination could improve deficits in an AD model, 8.5-month-old amyloid-β protein precursor 23 (AβPP23) mice. Co-administration of Am80 (0.5 mg/kg) and HX630 (5 mg/kg) for 17 days significantly improved memory deficits (Morris water maze) in AβPP23 mice, whereas administration of either agent alone produced no effect. Only co-administration significantly reduced the level of insoluble Aβ peptide in the …brain. These results thus indicate that effective memory improvement via reduction of insoluble Aβ peptide in 8.5-month-old AβPP23 mice requires co-activation of RARα,β and RXRs. RARα-positive microglia accumulated Aβ plaques in the AβPP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125 I-labeled oligomeric Aβ1-42 peptide in an insulin-degrading enzyme (IDE)-dependent manner. The co-administration increased mRNA for IDE and membrane-associated IDE protein in vivo, suggesting that IDE contributes to Aβ clearance in Am80/HX630-treated AβPP23 mice. Am80/HX630 also increased IL-4Rα expression in microglial MG5 cells. The improvement in memory of Am80/HX630-treated AβPP23 mice was correlated with the levels and signaling of hippocampal interleukin-4 (IL-4). Therefore, Am80/HX630 may promote differentiation of IL-4-responsive M2-like microglia and increase their activity for clearance of oligomeric Aβ peptides by restoring impaired IL-4 signaling in AβPP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy. Show more

Keywords: Alzheimer's disease, Am80, amyloid-β peptides, HX630, interleukin-4, memory improvement

DOI: 10.3233/JAD-132720

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 587-605, 2014

Authors: Hawkins, Kara M. | Sergio, Lauren E.

Article Type: Research Article

Abstract: Background and Objective: Recent evidence suggests that visuomotor behaviors may be disrupted in the very early stages of Alzheimer’s disease (AD). Here we propose that using kinematic measures under conditions that place demands on visual-spatial and cognitive-motor processing may provide an effective behavioral means to detect subtle changes associated with AD risk. Methods: To this end, we have tested 22 young adults (mean age = 26.4 ± 4.1) and 22 older adults (mean age = 64.3 ± 10.1) at low AD, and 22 older adults (mean age = 67.7 ± 11.3) at high AD risk (i.e., strong family …history or diagnosis of mild cognitive impairment). Kinematic measures were acquired on four visuomotor transformation tasks (standard, feedback reversal, plane dissociated, and plane dissociated + feedback reversal) using a dual-touchscreen tablet. Results: Comparing participants at increased AD risk with both young and old healthy control groups revealed significant performance disruptions in at-risk individuals as task demands increased. Furthermore, we were able to discriminate between individuals at high and low AD risk with a classification accuracy of 86.4% (sensitivity: 81.8%, specificity: 90.9%). Conclusion: We suggest that the impairments observed in individuals at increased AD risk may reflect inherent brain alteration and/or early neuropathology disrupting the reciprocal communication between hippocampal, parietal, and frontal brain regions required to successfully prepare and update complex reaching movements. Such impairment has the potential to affect activities of daily living, and may serve as a sensitive measure of functional ability in at-risk adults. Show more

Keywords: Aging, Alzheimer's disease, geriatric assessment, motor skills, movement, neurodegenerative disorder

DOI: 10.3233/JAD-140051

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 607-621, 2014

Authors: Conde-Sala, Josep L. | Turró-Garriga, Oriol | Calvó-Perxas, Laia | Vilalta-Franch, Joan | Lopez-Pousa, Secundino | Garre-Olmo, Josep

Article Type: Research Article

Abstract: Although numerous studies have examined caregiver burden in the context of Alzheimer's disease, discrepancies remain regarding the influence of certain factors. This study aimed to identify trajectories of caregiver burden in the context of Alzheimer's disease, as well as the factors associated with them. A cohort of patients and caregivers (n = 330) was followed up over three years. Growth mixture models were fitted to identify trajectories of caregiver burden according to scores on the Zarit Burden Interview (ZBI). A multilevel multinomial regression analysis was then conducted with the resulting groups and the patient and caregiver factors. In the sample …as a whole, burden increased during follow-up (F = 4.4, p = 0.004). Three groups were identified: G1 (initially high but decreasing burden), G2 (moderate but increasing burden), and G3 (low burden that increased slightly). Patients in G1 and G2 presented more neuropsychiatric symptoms and poorer functional status than did those in G3. Caregivers in G1 and G2 had poorer mental health. Spouses and, especially, adult children who lived with their parent (the patient) were more likely to belong to G2 (odds ratio [OR] 6.24; 95% CI 2.89–13.47), as were sole caregivers (OR 3.51; 95% CI 1.98–6.21). The patient factors associated with increased burden are neuropsychiatric symptoms and functional status, while among caregivers, being the sole carer, poor mental health, and living with the patient are of relevance. Show more

Keywords: Burden, family caregivers, longitudinal studies, mental health, neurobehavioral manifestations

DOI: 10.3233/JAD-140360

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 623-633, 2014

Authors: Edwards, Melissa | Balldin, Valerie Hobson | Hall, James | O'Bryant, Sid

Article Type: Research Article

Abstract: Background: Current work has sought to establish a rapid and cost effective means of screening for Alzheimer’s disease (AD) with the most recent findings showing utility of integrating blood-based biomarkers with cognitive measures. Objective: The current project sought to create a combined biomarker-cognitive profile to detect mild AD. Methods: Data was analyzed from 266 participants (129 AD cases [Early AD n = 93; Very Early AD n = 36]; 137 controls) enrolled in the Texas Alzheimer’s Research and Care Consortium (TARCC). Non-fasting serum samples were collected from each participant and assayed via a multi-plex biomarker assay …platform using electrochemiluminescence. Logistic Regression was utilized to detect early AD using two serum biomarkers (TNFα and IL7), demographic information (age), and one neuropsychological measure (Clock 4-point) as predictor variable. Disease severity was determined via Clinical Dementia Rating (CDR) scale global scores. Results: In the total sample (all levels of CDR scores), the combination of biomarkers, cognitive test score, and demographics yielded the obtained sensitivity (SN) of 0.94, specificity (SP) of 0.90, and an overall accuracy of 0.92. When examining early AD cases (i.e.m CDR = 0.5–1), the biomarker-cognitive profile yielded SN of 0.94, SP of 0.85, and an overall accuracy of 0.91. When restricted to very early AD cases (i.e., CDR = 0.5), the biomarker-cognitive profile yielded SN of 0.97 and SP of 0.72, with an overall accuracy of 0.91. Conclusions: The combination of demographics, two biomarkers, and one cognitive test created a biomarker-cognitive profile that was highly accurate in detecting the presence of AD, even in the very early stages. Show more

Keywords: Alzheimer's disease, biomarkers, molecular, neuropsychology

DOI: 10.3233/JAD-140852

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 635-640, 2014

Authors: Keage, Hannah A.D. | Hunter, Sally | Matthews, Fiona E. | Ince, Paul G. | Hodges, John | Hokkanen, Suvi R.K. | Highley, J. Robin | Dening, Tom | Brayne, Carol | On behalf of the Cambridge City over 75s Cohort

Article Type: Research Article

Abstract: Background: The significance of TDP-43 pathology in relation to aging and dementia in the population is unclear. Objective: We aimed to determine the prevalence of transactive response DNA-binding protein of 43 kDA (TDP-43) neuronal inclusions in a population-based sample, and associations with age group at death (≤90 and >90 years) and clinical dementia status prior to death. Further, we investigate associations between TDP-43 inclusions and other key dementia-related neuropathologies (plaques, tangles, and neuronal loss) within the hippocampus and entorhinal and temporal cortices. Methods: All brain donors within the Cambridge City over-75 s Cohort (CC75C), which is …population-based and longitudinally tracked (n = 228), were included. Age at death ranged from 78 to 106 years. TDP-43 neuronal inclusions were assessed in the hippocampus, entorhinal cortex, and temporal cortex. These data were combined with existing clinical and neuropathological data. Results: TDP-43 neuronal inclusions were present in 27% of the sample, 36% of those with clinical dementia and 18% without dementia. Individuals who died later (>90 years) or with clinical dementia were more likely to show TDP-43 inclusions. Hippocampal and entorhinal TDP-43 inclusions were significantly associated with dementia severity and increasing age, taking into account other neuropathologies. TDP-43 neuronal inclusions appeared to be co-localize with severe neuronal loss. Conclusion: Findings indicate that hippocampal and entorhinal TDP-43 inclusions are important substrates of late onset dementia which appear to co-localize with severe neuronal loss, but not with Alzheimer’s disease markers of amyloid and tau. This broadens the accepted view of TDP-43 pathology in dementias. Show more

Keywords: Aging, Alzheimer's disease, aging, dementia, population, TDP-43

DOI: 10.3233/JAD-132351

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 641-650, 2014

Authors: Peter, Jessica | Abdulkadir, Ahmed | Kaller, Christoph | Kümmerer, Dorothee | Hüll, Michael | Vach, Werner | Klöppel, Stefan | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Although episodic memory impairment is usually the earliest sign of Alzheimer's disease (AD), there are up to 15% of patients presenting with early impairment in non-memory cognitive functions (i.e., atypical AD). Stratifying patients with AD may aid clinical trials. Previous studies divided patients by cognitive profile, focusing on cross-sectional analyses without testing stability of clusters over time. We used principal component analysis followed by cluster analyses in 127 patients with AD based on 24 cognitive scores at 0, 6, 12, and 24 months follow-up. We investigated the definition of clusters and their stability over time as well as interactions of …cluster assignment and disease severity. At each time point, six distinct factors and four distinct clusters were extracted that did not differ substantially between time points. Clusters were defined by cognitive profile rather than disease severity. 85% of patients fell into the same cluster twice, 42% three times, and 17% four times. Subjects with focal semantic impairment progressed significantly faster than the other cluster. Longitudinally, focal deficits increased relatively rather than tending toward average disease severity. The observed similar cluster definitions at each time point indicate the validity of the approach. Cluster-specific longitudinal increases of focal impairments and significant between-cluster differences in disease progression make this approach useful for stratified inclusion into clinical trials. Show more

Keywords: Alzheimer's disease, atypical AD, cluster analysis, clustering, subgroups, subtypes, typical AD

DOI: 10.3233/JAD-140261

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 651-661, 2014

Authors: Wang, Chong | Yu, Jin-Tai | Wang, Hui-Fu | Tan, Chen-Chen | Meng, Xiang-Fei | Tan, Lan

Article Type: Research Article

Abstract: Background: Non-pharmacological interventions, including cognition-based intervention and physical exercise, are available for mild cognitive impairment (MCI), but their efficacy remains uncertain. Objective: To evaluate efficacy of cognition-based intervention and physical exercise on cognitive domains in patients with MCI. Methods: We searched MEDLINE, EMBASE, the Cochrane library, and BIOSIS previews to identify randomized controlled trials (RCTs) that involved cognition-based intervention and physical exercise for persons who were diagnosed with MCI. The pooled weight mean difference or standard mean difference (SMD) were calculated using a random-effect model. Results: We found significant effects of cognition-based intervention on …global cognitive function (SMD 0.37 [0.07, 0.68] p = 0.02). Besides, cognition-based intervention produced significant effects on executive function reported with TMT-B (SMD 0.8 [0.09, 1.5] p = 0.03) and delayed memory (SMD 0.31 [0.01, 0.61] p = 0.05). A beneficial improvement in global cognitive function was also seen in the exercise group compared to the control group (SMD 0.25 [0.08, 0.41] p = 0.003). Conclusions: Both of cognition-based intervention and physical exercise had the potential to improve global cognitive function. Weak evidence of improvements was also observed for the domains of executive function and delayed memory following cognition-based intervention. Nevertheless, future standard RCTs are still needed to identify the clinical value of our results. Show more

Keywords: Cognition-based intervention, cognitive function, exercise, meta-analysis, mild cognitive impairment, non-pharmacological interventions

DOI: 10.3233/JAD-140660

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 663-678, 2014

Authors: Tao, Yunlong | Wang, Yu | Rogers, Jack T. | Wang, Fudi

Article Type: Research Article

Abstract: Background: The homeostasis and physiological role of iron in Alzheimer’s disease (AD) has been debated for decades. Overall, it has been difficult to reach a consensus to prove marked disease-associated changes in the iron content of the AD brain, blood, or cerebrospinal fluid (CSF). Objectives: We sought to contribute to resolve this issue by quantifying the iron content in serum, CSF, and sub-regions of the AD brain. Methods: We conducted a comprehensive systematic meta-analysis and review of multiple observational studies till October 2013 that investigated the iron content in AD serum, CSF, or brain tissue. …Results: 2,556 publications were screened. Forty-three eligible studies with 1,813 AD patients and 2,401 healthy controls were identified. Twenty-one studies investigated the serum iron in AD while seven and nineteen studies investigated the CSF iron and various brain regions iron respectively. Our meta-analysis showed that serum iron was significant lower in AD than healthy controls. CSF iron appeared not to be affected by AD although more studies are required due to the relative small number of CSF studies reported to date. We critically analyzed iron content in twelve selective brain regions by separated meta-analyses using cross-referenced statistical methods. We found that eight specific brain regions had higher iron concentrations that correlated with the clinical diagnosis of AD in a statistically validated manner. Conclusions: These data provided rigorous statistical support for the model that iron homeostasis was changed in AD patients, including the finding of lower iron in their serum and evidence for iron overload in several specific brain regions. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, iron, iron overload, meta-analysis, serum iron, systematic review

DOI: 10.3233/JAD-140396

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 679-690, 2014

Authors: Guo, Hui | Song, Xiaowei | Schmidt, Matthias H. | Vandorpe, Robert | Yang, Zhan | LeBlanc, Emily | Zhang, Jing | Beyea, Steven | Zhang, Yunting | Rockwood, Kenneth | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The Brain Atrophy and Lesion Index (BALI), a semi-quantitative rating scale, has been developed to evaluate whole brain structural changes in aging and Alzheimer’s disease (AD). Objective: This study describes a standard procedure to score the BALI and train new raters for reliable BALI evaluation following this procedure. Methods: Structural MRI of subjects in the Alzheimer’s Disease Neuroimaging Initiative dataset who had 3.0T, T1, and T2 weighted MRI scans at baseline and at 6, 12, and 24 month follow-ups were retrieved (n = 122, including 24 AD, 51 mild cognitive impairment patients, and 47 healthy …control subjects). Images were evaluated by four raters following training with a step-by-step BALI process. Seven domains of structural brain changes were evaluated, and a total score was calculated as the sum of the sub-scores. Results: New raters achieved >90% accuracy after two weeks of training. Reliability was shown in both intra-rater correlation coefficients (ICC ≥ 0.92, p < 0.001) and inter-rater correlation coefficients (ICC ≥0.88, p < 0.001). Mean BALI total scores differed by diagnosis (F ≥ 2.69, p ≤ 0.049) and increased consistently over two years. Conclusion: The BALI can be introduced using a standard procedure that allows new users to achieve highly reliable evaluation of structural brain changes. This can advance its potential as a robust method for assessing global brain health in aging, AD, and mild cognitive impairment. Show more

Keywords: Aging, Alzheimer's disease, brain, Brain Atrophy and Lesion Index (BALI), cognition, structural MRI

DOI: 10.3233/JAD-140333

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 691-703, 2014

Article Type: Other

DOI: 10.3233/JAD-140334

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 705-706, 2014