Journal of Alzheimer's Disease - Volume 41, issue 2

Authors: Korecka, Magdalena | Waligorska, Teresa | Figurski, Michal | Toledo, Jon B. | Arnold, Steven E. | Grossman, Murray | Trojanowski, John Q. | Shaw, Leslie M.

Article Type: Research Article

Abstract: The primary aims of this work were to: 1) establish a calibrator surrogate matrix for quantification of amyloid-β (Aβ)42 in human cerebrospinal fluid (CSF) and preparation of quality control samples for LC-MS-MS methodology, 2) validate analytical performance of the assay, and 3) evaluate its diagnostic utility and compare it with the AlzBio3 immunoassay. The analytical methodology was based on a 2D-UPLC-MS-MS platform. Sample pretreatment used 5 M guanidine hydrochloride and extraction on μElution SPE columns as previously described. A column cleaning procedure involved gradual removal of aqueous solvents by acetonitrile assured consistent long-term chromatography performance. Receiver-operator characteristic (ROC) curve …and correlation analyses evaluated the diagnostic utility of UPLC-MS-MS compared to AlzBio3 immunoassay for detection of Alzheimer's disease (AD). The surrogate matrix, artificial CSF containing 4 mg/mL of BSA, provides linear and reproducible calibration comparable to human pooled CSF as calibration matrix. Appropriate cleaning of the trapping and analytical columns provided every-day, trouble-free runs. Analyses of CSF Aβ42 showed that UPLC-MS-MS distinguished neuropathologically-diagnosed AD subjects from healthy controls with at least equivalent diagnostic utility to AlzBio3. Comparison of ROC curves for these two assays showed no statistically significant difference (p = 0.2229). Linear regression analysis of Aβ42 concentrations measured by this mass spectrometry-based method compared to the AlzBio3 immunoassay showed significantly higher but highly correlated results. In conclusion, the newly established surrogate matrix for 2D-UPLC-MS-MS measurement of Aβ42 provides selective, reproducible, and accurate results. The documented analytical performance and diagnostic performance for AD versus controls supports consideration as a candidate reference method. Show more

Keywords: Alzheimer's disease, amyloid-β42, cerebrospinal fluid, mass spectrometry

DOI: 10.3233/JAD-132489

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 441-451, 2014

Authors: Rami, Lorena | Mollica, Maria A. | García-Sanchez, Carmen | Saldaña, Judith | Sanchez, Belen | Sala, Isabel | Valls-Pedret, Cinta | Castellví, Magda | Olives, Jaume | Molinuevo, Jose L.

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is gaining importance as a focus of investigation, but adequate tools are needed for its quantification. Objective: To develop and validate a questionnaire to quantify SCD, termed the Subjective Cognitive Decline Questionnaire (SCD-Q). Methods: 124 controls (CTR), 144 individuals with SCD, 83 mild cognitive impairment subjects, 46 Alzheimer’s disease patients, and 397 informants were included. The SCD-Q contains: part I, named MyCog, which is answered by the subject; and part II, TheirCog, which includes the same questions and is answered by the informant or caregiver. The 24 SCD-Q items assess the …perceived subjective decline in memory, language, and executive functions in the last two years. Results: The MyCog scores of controls differed significantly from those of the other groups (p < 0.05) and there were significant differences in TheirCog scores between all groups. The optimal TheirCog cut-off score for discriminating between individuals with and without cognitive impairment was 7/24 (sensitivity 85%, specificity 80%). MyCog scores correlated significantly with anxiety and depression (r = 0.29, r = 0.43, p < 0.005), but no correlations were found with neuropsychological tests. TheirCog scores correlated significantly with most of the neuropsychological tests (p < 0.05). Informants’ depression and anxiety influenced TheirCog scores in controls and SCD groups. Conclusion: Self-perceived cognitive decline, measured by the SCD-Q part I (MyCog), discriminated SCD from CTR. Part II (TheirCog) was strongly related to subjects’ objective cognitive performance, and discriminated between subjects with or without cognitive impairment. The SCD-Q is a useful tool to measure self-perceived cognitive decline incorporating the decliner and the informant perspective. Show more

Keywords: Alzheimer's disease, cognition, diagnosis, memory, test

DOI: 10.3233/JAD-132027

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 453-466, 2014

Authors: Garcia-Ptacek, Sara | Farahmand, Bahman | Kåreholt, Ingemar | Religa, Dorota | Cuadrado, Maria Luz | Eriksdotter, Maria

Article Type: Research Article

Abstract: Background: Knowledge on survival in dementia is crucial for patients and public health planning. Most studies comparing mortality risk included few different dementia diagnoses. Objectives: To compare mortality risk in the most frequent dementia disorders in a large cohort of patients with an incident diagnosis, adjusting for potential confounding factors. Methods: 15,209 patients with dementia from the national quality database, Swedish Dementia Registry (SveDem), diagnosed in memory clinics from 2008 to 2011, were included in this study. The impact of age, gender, dementia diagnosis, baseline Mini-Mental State Examination (MMSE), institutionalization, coresidency, and medication on survival after …diagnosis were examined using adjusted hazard ratios (HR) with 95% confidence intervals (CI). Results: During a mean follow-up of 2.5 years, 4,287 deaths occurred, with 114 (95% CI 111–117) deaths/1,000 person-years. Adjusted HR of death for men was 1.56 (95% CI 1.46–1.66) compared to women. Low MMSE, institutionalization, and higher number of medications were associated with higher HR of death. All dementia diagnoses demonstrated higher HR compared to Alzheimer’s disease, with vascular dementia presenting the highest crude HR. After adjusting, frontotemporal dementia had the highest risk with a HR of 1.91 (95% CI 1.52–2.39), followed by Lewy body dementia (HR 1.64; 95% CI 1.39–1.95), vascular dementia (HR 1.55; 95% CI 1.42–1.69), Parkinson’s disease dementia (HR 1.47; 95% CI 1.17–1.84), and mixed Alzheimer’s disease and vascular dementia (HR 1.32; 95% CI 1.22–1.44). Conclusion: Worse cognition, male gender, higher number of medications, institutionalization, and age were associated with increased death risk after dementia diagnosis. Adjusted risk was lowest in Alzheimer’s disease patients and highest in frontotemporal dementia subjects. Show more

Keywords: Alzheimer's disease, cohort studies, dementia, frontotemporal dementia, mortality, Parkinson's disease, vascular dementia

DOI: 10.3233/JAD-131856

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 467-477, 2014

Authors: Dlugaj, Martha | Weinreich, Gerhard | Weimar, Christian | Stang, Andreas | Dragano, Nico | Wessendorf, Thomas E. | Teschler, Helmut | Winkler, Angela | Wege, Natalia | Moebus, Susanne | Möhlenkamp, Stefan | Erbel, Raimund | Jöckel, Karl-Heinz | on behalf of the Heinz Nixdorf Recall Study Investigative Group

Article Type: Research Article

Abstract: There is increasing evidence that sleep disorders are associated with cognitive decline. We, therefore, examined the cross-sectional association of sleep-disordered breathing (SDB), sleep quality, and three types of sleep complaints (difficulties initiating sleep, difficulties maintaining sleep, and early morning awakening) with mild cognitive impairment (MCI) and its subtypes. A group of 1,793 participants (51% men; 63.8 ± 7.5 years) of the population-based Heinz Nixdorf Recall study (total sample n = 4,157) received a screening for SDB and self-report measures of sleep complaints. Group comparisons were used to compare performances among five cognitive subtests. Multivariate logistic regression models were calculated to …determine the association of MCI (n = 230) and MCI subtypes (amnestic MCI, n = 120; non-amnestic MCI, n = 110) with SDB severity levels, poor sleep quality, and sleep complaints. Severe SDB (apnea-hypopnea index ≥30/h, n = 143) was not associated with MCI, amnestic MCI, or non-amnestic MCI. Poor sleep quality was associated with MCI (Odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.02–2.03; fully adjusted) as well as frequently reported difficulties initiating sleep (OR = 1.94, 1.20–3.14), difficulties maintaining sleep (OR = 2.23, 1.27–4.63), and early morning awakening (OR = 2.30, 1.32–4.00). Severe difficulties initiating sleep (OR = 2.23, 1.21–4.13) and early morning awakening (OR = 2.88, 1.45–5.73) were solely associated with the amnestic MCI subtype, whereas, severe difficulties maintaining sleep (OR = 3.84, 1.13–13.08) were associated with non-amnestic MCI. Our results suggest that poor sleep quality, rather than SDB, is associated with MCI. The selective association of difficulties initiating sleep and early morning awakening with amnestic MCI and of difficulties maintaining sleep with non-amnestic MCI might serve as a marker to improve diagnostic accuracy in the earliest stages of cognitive impairment and will be further investigated in our longitudinal examination. Show more

Keywords: Aging, difficulties initiating sleep, difficulties maintaining sleep, early morning awakening, mild cognitive impairment, sleep-disordered breathing

DOI: 10.3233/JAD-132132

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 479-497, 2014

Authors: Shao, Haijun | Zhang, Yiying | Dong, Yuanlin | Yu, Buwei | Xia, Weiming | Xie, Zhongcong

Article Type: Research Article

Abstract: There is a need to seek new treatment(s) for Alzheimer's disease (AD). A recent study showed that AD patients may have decreased levels of functional GABA receptors. Propofol, a commonly used anesthetic, is a GABA receptor agonist. We therefore set out to perform a proof of concept study to determine whether chronic treatment with propofol (50 mg/kg/week) can improve cognitive function in both aged wild-type (WT) and AD transgenic (Tg) mice. Propofol was administrated to the WT and AD Tg mice once a week for 8 or 12 weeks, respectively. Morris water maze was used to assess the cognitive function …of the mice following the propofol treatment. Activation of caspase-3, caspase-9, and caspase-8 was investigated using western blot analysis at the end of the propofol treatment. In the mechanistic studies, effects of propofol, amyloid-β protein (Aβ), and GABA receptor antagonist flumazenil on caspase-3 activation and opening of the mitochondrial permeability transition pore were assessed in H4 human neuroglioma and mouse neuroblastoma cells by western blot analysis and flow cytometry. Here we showed that the propofol treatment improved cognitive function and attenuated brain caspase-3 and caspase-9 activation in both aged WT and AD Tg mice. Propofol attenuated Aβ-induced caspase-3 activation and opening of the mitochondrial permeability transition pore in the cells, and flumazenil inhibited the propofol's effects. These results suggested that propofol might improve cognitive function via attenuating the Aβ-induced mitochondria dysfunction and caspase activation, which explored the potential that anesthetic propofol could improve cognitive function in elderly and AD patients. Show more

Keywords: Aging, Alzheimer's disease, amyloid-β protein, anesthesia, apoptosis, mitochondria, neurodegeneration, propofol

DOI: 10.3233/JAD-132792

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 499-513, 2014

Authors: Torkamani, Mariam | McDonald, Louise | Aguayo, Ignasi Saez | Kanios, Christos | Katsanou, Maria-Nefeli | Madeley, Laura | Limousin, Patricia D. | Lees, Andrew J. | Haritou, Maria | Jahanshahi, Marjan | the ALADDIN Collaborative Group

Article Type: Research Article

Abstract: The use of telemedicine is becoming increasingly popular in assisting with the home management of People with Dementia (PwD) by offering services to the carers that may enhance their ability to care for their relative for longer. A computerized platform, ALADDIN, was evaluated in its usefulness to reduce carer burden and distress and to improve their quality of life, in an attempt to delay institutionalization of PwD. ALADDIN offers educational material about dementia to carers and provides the opportunity to contact other carers and clinicians. ALADDIN also facilitates remote monitoring of the PwD and their carers by the clinicians to …enable speedy delivery of appropriate intervention. The ALADDIN platform was piloted at three European sites, and used by thirty carers of PwD living in the community (platform group). The platform group and a control group of thirty PwD and their carers were assessed at baseline, 3 months, and 6 months. The results showed a significant improvement in the quality of life of the carers in the platform group, with some reduction in carer burden and distress. The platform was useful in monitoring the patients and facilitating contact with other professionals. Access to and use of the ALADDIN platform was rated positively by carers and clinicians. The ALADDIN platform's usefulness and applicability for prolonging the home management of PwD are discussed. Show more

Keywords: Carer burden, dementia, distress, institutionalization, quality of life, telecare, telemedicine

DOI: 10.3233/JAD-132156

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 515-523, 2014

Authors: Khemka, Vineet Kumar | Bagchi, Debajit | Bandyopadhyay, Kausik | Bir, Aritri | Chattopadhyay, Mrittika | Biswas, Atanu | Basu, Debasis | Chakrabarti, Sasanka

Article Type: Research Article

Abstract: Cerebral hypometabolism of glucose, weight loss, and decreased food intake are characteristic features of sporadic Alzheimer's disease (AD). A systematic study on the serum levels of adipokines and insulin, the major hormones regulating energy metabolism, food intake, and body weight, in sporadic AD is necessary. The present study compares the serum levels of leptin, adiponectin, and insulin, measured by commercially available immuno-assay kits, between controls and sporadic AD subjects. The results show a conspicuous decrease in the level of leptin, a dramatic rise in the level of adiponectin, and also a statistically significant increase in insulin level, in the blood …of AD subjects, with respect to controls. The changes in the serum levels of adiponectin and insulin in AD are positively correlated with the severity of dementia. Likewise, the serum level of leptin in AD subjects is negatively correlated with the degree of dementia. The changes in the levels of adipokines and insulin have implications in the amyloid pathology, neurodegeneration, and hypometabolism of glucose existing in the AD brain. Show more

Keywords: Adiponectin, Alzheimer's disease, amyloid-β, insulin, leptin

DOI: 10.3233/JAD-140006

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 525-533, 2014

Authors: Fitz, Nicholas F. | Castranio, Emilie L. | Carter, Alexis Y. | Kodali, Ravindra | Lefterov, Iliya | Koldamova, Radosveta

Article Type: Research Article

Abstract: Passive amyloid-β (Aβ) vaccination has shown significant effects on amyloid pathology in pre-depositing amyloid-β protein precursor (AβPP) mice but the results in older mice are inconsistent. A therapeutic effect of LXR and RXR agonists consisting of improved memory deficits and Aβ pathology has been demonstrated in different Alzheimer's disease (AD) mouse models. Here, we report the effect of a combination of N-terminal Aβ antibody and synthetic LXR agonist T0901317 (T0) on AD-like phenotype of APP23 mice. To examine the therapeutic potential of this combination, the treatment of mice started at 11 months of age, when amyloid phenotype in this model …is fully developed, and continued for 50 days. We show that Aβ immunization with or without LXR agonist restored the performance of APP23 transgenic mice in two behavior paradigms without affecting the existing amyloid plaques. Importantly, we did not observe an increase of brain microhemorrhage which is considered a significant side effect of Aβ vaccination. Target engagement was confirmed by increased Abca1 and ApoE protein level as well as increased ApoE lipidation in soluble brain extract. In interstitial fluid obtained by microdialysis, we demonstrate that immunization and T0 significantly reduced Aβ levels, indicating an increased Aβ clearance. We found no interaction between the immunotherapy and T0, suggesting no synergism, at least with these doses. The results of our study demonstrate that anti-Aβ treatments can ameliorate cognitive deficits in AβPP mice with advanced AD-like phenotype in conjunction with a decrease of Aβ in brain interstitium and increase of ApoE lipidation without affecting the existing amyloid plaques. Show more

Keywords: Abca1, ApoE lipidation, APP23 mice, amyloid-β immunization, amyloid plaques, fear conditioning, interstitial fluid, LXR agonist, microdialysis, radial water maze

DOI: 10.3233/JAD-132789

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 535-549, 2014

Authors: Hussain, Shafaat | Mansouri, Shiva | Sjöholm, Åke | Patrone, Cesare | Darsalia, Vladimer

Article Type: Research Article

Abstract: Type 2 diabetes (T2D) is strongly associated with early cognitive decline and may facilitate the development of neurodegenerative diseases. Despite the overwhelming amount of indirect evidence pointing toward the presence of cerebral neurodegeneration in T2D, no hard proof of it on histological and quantitative levels exists. This warrants more research to investigate whether T2D can lead to neurodegeneration in the central nervous system and to study the precise nature and temporal dynamics of such changes. We performed a comprehensive quantitative assessment of T2D-induced changes in neuronal and glial numbers in the cerebral cortex using stereological methods. We compared the cellular …composition of 3- and 13-month-old male type 2 diabetic Goto-Kakizaki (GK) rat brains. Age and sex-matched Wistar rats served as healthy controls. Our results show a significant decrease in neuron numbers (≈11%) in the cerebral cortex of 13-month-old GK rats compared to young, or Wistar rats, while astroglia numbers were unchanged. We also recorded increased microglia activation in aged diabetic rat brains as indicated by significantly increased average microglia cell volume. Our observations provide quantitative evidence of T2D-induced changes in brain's cellular composition during aging. These findings may facilitate the mechanistic understanding of cognitive dysfunction and other neurodegenerative disorders in T2D. Show more

Keywords: Aging, cerebral cortex, diabetes, GK rat, neurodegeneration

DOI: 10.3233/JAD-131958

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 551-560, 2014

Authors: Coskuner, Orkid | Murray, Ian V.J.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a devastating disease of aging that initiates decades prior to clinical manifestation and represents an impending epidemic. Two early features of AD are metabolic dysfunction and changes in amyloid-β protein (Aβ) levels. Since levels of ATP decrease over the course of the disease and Aβ is an early biomarker of AD, we sought to uncover novel linkages between the two. First and remarkably, a GxxxG motif is common between both Aβ (oligomerization motif) and nucleotide binding proteins (Rossmann fold). Second, ATP was demonstrated to protect against Aβ mediated cytotoxicity. Last, there is structural similarity between ATP …and amyloid binding/inhibitory compounds such as ThioT, melatonin, and indoles. Thus, we investigated whether ATP alters misfolding of the pathologically relevant Aβ42 . To test this hypothesis, we performed computational and biochemical studies. Our computational studies demonstrate that ATP interacts strongly with Tyr10 and Ser26 of Aβ fibrils in solution. Experimentally, both ATP and ADP reduced Aβ misfolding at physiological intracellular concentrations, with thresholds at ~500 μM and 1 mM respectively. This inhibition of Aβ misfolding is specific; requiring Tyr10 of Aβ and is enhanced by magnesium. Last, cerebrospinal fluid ATP levels are in the nanomolar range and decreased with AD pathology. This initial and novel finding regarding the ATP interaction with Aβ and reduction of Aβ misfolding has potential significance to the AD field. It provides an underlying mechanism for published links between metabolic dysfunction and AD. It also suggests a potential role of ATP in AD pathology, as the occurrence of misfolded extracellular Aβ mirrors lowered extracellular ATP levels. Last, the findings suggest that Aβ conformation change may be a sensor of metabolic dysfunction. Show more

Keywords: Amyloid-β, ATP, cerebrospinal fluid, metabolic dysfunction

DOI: 10.3233/JAD-132300

Citation: Journal of Alzheimer's Disease, vol. 41, no. 2, pp. 561-574, 2014