Journal of Alzheimer's Disease - Volume 46, issue 1

Authors: Li, Gongbo | Kim, Chaeyoung | Kim, Jaekwang | Yoon, Hyejin | Zhou, Huadong | Kim, Jungsu

Article Type: Research Article

Abstract: While early-onset familial Alzheimer’s disease (AD) is caused by a genetic mutation, the vast majority of late-onset AD is likely caused by the combination of genetic and environmental factors. Unlike genetic studies, potential environmental factors affecting AD pathogenesis have not yet been thoroughly investigated. Among environmental factors, pesticides seem to be one of critical environmental contributors to late-onset AD. Recent studies reported that the serum and brains of AD patients have dramatically higher levels of a metabolite of dichlorodiphenyltrichloroethane (DDT). While these epidemiological studies provided initial clues to the environmental risks potentially contributing to disease pathogenesis, a functional approach is …required to determine whether they actually have a causal role in disease development. In our study, we addressed this critical knowledge gap by investigating possible mechanisms by which DDT affects amyloid-β (Aβ) levels. We treated H4-AβPPswe or H4 cells with DDT to analyze its effect on Aβ metabolism using Aβ production, clearance, and degradation assays. We found that DDT significantly increased the levels of amyloid-β protein precursor (AβPP) and β-site AβPP-cleaving enzyme1 (BACE1), affecting Aβ synthesis pathway in H4-AβPPswe cells. Additionally, DDT impaired the clearance and extracellular degradation of Aβ peptides. Most importantly, we identified for the first time that ATP-binding cassette transporter A1 (ABCA1) and insulin-degrading enzyme (IDE) are the downstream target genes adversely affected by DDT. Our findings provide insight into the molecular mechanisms by which DDT exposure may increase the risk of AD, and it further supports that ABCA1 and IDE may be potential therapeutic targets. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, ATP-binding cassette transporter A1, β-site AβPP-cleaving enzyme1, dichlorodiphenyldichloroethylene, dichlorodiphenyltrichloroethane, insulin-degrading enzyme, pesticides

DOI: 10.3233/JAD-150024

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 109-122, 2015

Authors: Bhattacharya, Soumee | Maelicke, Alfred | Montag, Dirk

Article Type: Research Article

Abstract: The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimer’s disease (AD), providing cognitive and global relief in human patients. However, as an acetylcholinesterase inhibitor, gastrointestinal side effects limit the dosage and duration of treatment. Memogain (Gln-1062), a pro-drug, liberates galantamine on cleavage by a carboxyesterase in the brain. The possibility to deliver Memogain intranasally may further circumvent side effects, allowing higher dosing compared to galantamine. In this study, the 5X Familial Alzheimer’s Disease (5XFAD) mouse model was used to investigate the effect of chronic Memogain treatment on behavior and amyloid-β (Aβ) plaque deposition in the brain. Chronic …intranasal dosage of 6 mg/kg body weight twice daily was tolerated well, whereas the double dose caused body weight loss in males and was less effective in some behavioral tests. 8 weeks of chronic treatment resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, and in fear conditioning already at mildly affected stages at the age of 18 weeks compared to untreated controls. Furthermore, after treatment a significantly lower plaque density in the brain, i.e., in the entorhinal cortex (reduction 20% females, 40% males) and the hippocampus (19% females, 31% males) at the age of 18 weeks was observed. These results show that nasal application of Memogain effectively delivers the drug to the brain with the potential to retard plaque deposition and improve behavioral symptoms in AD similar to the approved galantamine. Show more

Keywords: Acetylcholinesterase inhibitor, Alzheimer’s disease, amyloid plaques, galantamine, nasal application, nicotinic enhancer

DOI: 10.3233/JAD-142421

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 123-136, 2015

Authors: Haratz, Salo | Weinstein, Galit | Molshazki, Noa | Beeri, Michal Schnaider | Ravona-Springer, Ramit | Marzeliak, Oleg | Goldbourt, Uri | Tanne, David

Article Type: Research Article

Abstract: Background and Objective: Patients with pre-existing atherothrombotic disease are prone to cognitive impairment. We tested whether impaired cerebrovascular reactivity (CVR), a marker of cerebral microvascular hemodynamic dysfunction, is associated with poorer cognitive scores among patients with and without carotid large-vessel disease. Methods: A subgroup of non-demented patients with chronic coronary heart disease followed-up for 15 ± 3 years was assessed for cognitive function (Neurotrax Computerized Cognitive Battery; scaled to an IQ style scale with a mean of 100 and SD of 15) and for CVR using the breath-holding index (BHI) with transcranial Doppler and for carotid plaques …using ultrasound. We assessed cognitive scores in specific domains in patients with and without impaired CVR (BHI <0.47; bottom quartile). Results: Among 415 patients (mean age 71.7 ± 6.2 y) median BHI was 0.73 (25% 0.47, 75% 1.04). Impaired CVR was associated with diabetes and peripheral artery disease. Adjusting for potential confounders, impaired CVR was associated with lower executive function (p  = 0.02) and global cognitive scores (p  = 0.04). There was an interaction with carotid large-vessel disease for executive function (p  <  0.001), memory (p  = 0.03), and global cognitive scores (p  = 0.02). In the carotid large-vessel disease group there were pronounced differences by CVR status in executive function (p  <  0.001), memory (p  = 0.02), attention (p  <  0.001), and global cognitive scores (p  = 0.001). Conclusion: Impaired CVR, a marker of cerebral microvascular dysfunction, is associated with poorer cognitive functions and in particular executive dysfunction among non-demented patients with concomitant carotid large-vessel disease. These findings emphasize the importance of cerebral hemodynamics in cognitive performance. Show more

Keywords: Cerebrovascular disorders, dementia, hemodynamics, transcranial Doppler sonography, vascular dementia

DOI: 10.3233/JAD-150052

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 137-144, 2015

Authors: Bik-Multanowski, Miroslaw | Pietrzyk, Jacek J. | Midro, Alina

Article Type: Research Article

Abstract: Morphological abnormalities observed typically in the brains of adults with Down syndrome are identical with those present in patients with Alzheimer’s disease. However, only some adults with Down syndrome suffer from early dementia, whereas others remain unaffected. We aimed to identify the genomic background responsible for this observation. We performed cognitive assessment and genome expression analysis of blood mononuclear cells in seniors with Down syndrome. Unaffected elderly patients and younger patients with severe cognitive disability or cognitive deterioration differed significantly with regard to the MTRNR2L12 gene. Our findings suggest the potential value of this gene as a blood marker …of early dementia in individuals with Down syndrome. Show more

Keywords: Alzheimer’s disease, blood marker, cognitive assessment, Down syndrome, early dementia, microarrays

DOI: 10.3233/JAD-143030

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 145-150, 2015

Authors: Bregman, Noa | Regev, Keren | Moore, Orna | Giladi, Nir | Ash, Elissa

Article Type: Research Article

Abstract: Identification of individuals at high risk for developing dementia and Alzheimer’s disease is a major challenge. A “memory fair” is an enjoyable and affordable tool designed to reach local population at risk, mainly those with subjective cognitive impairment (SCI) or mild cognitive impairment. The fair included a free cognitive assessment and presentation on the importance of sleep, physical activity, cognitive training, and risk-factors and provided personalized recommendations. 160 individuals completed the evaluation (69.97 ± 9.01 y, 83% women). Average Montreal Cognitive Assessment Score (MoCA) was 24.73 ± 3.71. Six percent reported SCI and an upper estimate of mild cognitive impairment prevalence …was 30.7% . SCI was found to be a sensitive predictor for MoCA <26. Show more

Keywords: Alzheimer’s disease, dementia, mild cognitive impairment, prevention, screening, subjective cognitive impairment

DOI: 10.3233/JAD-142724

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 151-155, 2015

Authors: Terpening, Zoe | Lewis, Simon J.G. | Yee, Brendon J. | Grunstein, Ron R. | Hickie, Ian B. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Sleep-disordered breathing in middle-age and older adults has been shown to be linked to a range of neuropsychological deficits, but the extent to which these relationships are evident in older people ‘at risk’ of developing dementia in unknown. In this study, we aimed to determine whether changes in sleep-disordered breathing and sleep fragmentation during nocturnal sleep were related to neuropsychological dysfunction in patients with mild cognitive impairment. Forty-six patients with MCI (mean age = 66.1 y, sd = 8.4) and 40 age-matched healthy controls (mean age = 63.5 y, sd = 8.9) underwent psychiatric, medical, and neuropsychological assessment, in addition to overnight polysomnography and self-report questionnaires. Measures of …hypoxemia, sleep fragmentation, and sleep quality were derived including the apnoea-hypopnea index, oxygen desaturation index, percentage of total sleep time spent below 90% oxygen saturation, arousal index, sleep efficiency, and wake after sleep onset. Patients with MCI did not differ from healthy aging on any measure of sleep-disordered breathing or sleep fragmentation. In MCI, processing speed was negatively correlated with greater sleep time spent below 90% oxygen saturation and a higher apnoea-hypopnea index. In contrast, in the healthy aging, processing speed was negatively correlated with an increased oxygen desaturation index and the arousal index. Sleep-disordered breathing is evident in both healthy aging and MCI with associated decrements in processing speed. Future research is needed to determine the unique and synergistic effects of these differential associations, their potential to inform disease trajectory, and possible therapeutic interventions. Show more

Keywords: Dementia, mild cognitive impairment, risk factors, sleep-disordered breathing

DOI: 10.3233/JAD-141860

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 157-165, 2015

Authors: Zeifman, Lubov E. | Eddy, William F. | Lopez, Oscar L. | Kuller, Lewis H. | Raji, Cyrus | Thompson, Paul M. | Becker, James T.

Article Type: Research Article

Abstract: The purpose of this study was to identify, at the voxel level, brain regions associated with the time to develop mild cognitive impairment (MCI) or Alzheimer’s disease (AD) from normal cognition. We analyzed incident MCI (n  = 58) or AD (n  = 151) in 292 cognitively normal participants in the Cardiovascular Health Study–Cognition Study (mean age = 79.2 ± 3.6 years). We used segmented, modulated grey matter maps from 3D (spoiled gradient echo) MRI scans obtained in 1998/99 (with clinical follow-up through 2012) that were smoothed with a 3-D 4 mm Gaussian filter. We fit approximately 1.92 million voxel-level Cox proportional hazard models to examine …the grey matter volume effect on time to event, adjusting for age, sex, and diabetes. We used the significance threshold of p  <  0.005 with contiguity threshold of at least 68 voxels (false detection probability <2.5×10 −8 ). Areas within the mesial temporal lobe (MTL), anterior temporal lobe, hippocampus, and posterior cingulate gyrus were associated with time to MCI or AD. The presence of white matter lesions (a marker of small vessel disease in the brain) was associated with the volumes of the MTL and precuneus; MRI-identified infarcts also predicted MTL volume. These findings are important because we identified critical brain regions that predict a person’s increased likelihood of developing MCI or AD over a decade prior to the onset of clinical symptoms; these critical brain regions were themselves affected by the presence of vascular disease. Show more

Keywords: Alzheimer’s disease, Cox survival model, incidence, mild cognitive impairment, MRI

DOI: 10.3233/JAD-150047

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 167-178, 2015

Authors: Bacchetti, Tiziana | Vignini, Arianna | Giulietti, Alessia | Nanetti, Laura | Provinciali, Leandro | Luzzi, Simona | Mazzanti, Laura | Ferretti, Gianna

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is associated with oxidative damage of low density lipoproteins (ox-LDL). In order to investigate whether higher levels of ox-LDL are related to alterations of the activity of enzymes involved in lipid metabolism, we studied the activity of paraoxonase-1 (PON1) and platelet activating factor acetylhydrolase (PAF-AH) in AD patients and the relationship between biochemical markers and severity of the disease. Levels of ox-LDL, PON1 (paraoxonase, arylesterase, and lactonase activities), and PAF-AH activity were evaluated in plasma from 49 patients affected by AD and from 34 control subjects matched for gender and age. Our results demonstrated alterations in the …activities of PON1 and PAF-AH in AD patients compared to controls and showed, for the first time, a relationship between the activities of these enzymes, ox-LDL levels, and severity of the disease. A significant negative correlation was observed between the ratio PON1/PAF-AH and ox-LDL. Whatever the causes that contribute to a systemic oxidative stress in AD, our results have shown that AD patients exhibit higher PAF-AH activity than control subjects and higher ox-LDL. This phenomenon, in combination with diminished PON1 in these patients and, consequently, the relatively lower ratio PON1/PAF-AH activity, could contribute to inflammation and oxidative stress of plasma lipoproteins. Show more

Keywords: Alzheimer’s disease, high density lipoproteins, lipid peroxidation, low density lipoproteins, oxidative stress, paraoxonase-1 (PON1), platelet activating factor acetyl hydrolase (PAF-AH)

DOI: 10.3233/JAD-143096

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 179-186, 2015

Authors: Savage, Sharon A. | Piguet, Olivier | Hodges, John R.

Article Type: Research Article

Abstract: Background: Reduced insight commonly occurs in dementia and can be specific to one area of functioning. Despite recent models identifying a role for semantic memory, little investigation of insight has been conducted in semantic dementia (SD), with patients often described as being aware of their language problems. Objective: This study aims to investigate language insight in SD. Method: Twenty-two SD (n  = 11 severe, n  = 11 mild-moderate) and 9 nonfluent primary progressive aphasic patients completed three experimental language tasks to assess knowledge and awareness of certain words. Skills in evaluating language were tested by comparing performance …ratings on the Cookie Theft task with objective scoring. Awareness regarding the existence and previous use of certain words was tested using two additional tasks. Results: While SD patients were as accurate as nonfluent patients in rating their own performance on the Cookie Theft immediately following the task, they were significantly poorer at evaluating the same content re-recorded, or other examples of poor language. Compared to nonfluent patients, severe SD patients also made more errors identifying previously known low frequency words. Lastly, when tested on labels for specific aspects of an object, only SD patients made errors regarding the existence, or their past knowledge, of certain words. Conclusion: SD patients show a general awareness of their language impairments, but have difficulty evaluating language content. These difficulties adversely affect the ability to reflect upon current and past language skills producing an under-awareness of language deficits. This mild, secondary form of anosognosia appears to increase with greater levels of semantic impairment. Show more

Keywords: Anosognosia, cognitive awareness, frontotemporal dementia, primary progressive aphasia, self-appraisal

DOI: 10.3233/JAD-142703

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 187-198, 2015

Authors: Suppa, Per | Hampel, Harald | Spies, Lothar | Fiebach, Jochen B. | Dubois, Bruno | Buchert, Ralph | and Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Hippocampus volumetry based on magnetic resonance imaging (MRI) has not yet been translated into everyday clinical diagnostic patient care, at least in part due to limited availability of appropriate software tools. In the present study, we evaluate a fully-automated and computationally efficient processing pipeline for atlas based hippocampal volumetry using freely available Statistical Parametric Mapping (SPM) software in 198 amnestic mild cognitive impairment (MCI) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI1). Subjects were grouped into MCI stable and MCI to probable Alzheimer’s disease (AD) converters according to follow-up diagnoses at 12, 24, and 36 months. Hippocampal grey matter volume …(HGMV) was obtained from baseline T1-weighted MRI and then corrected for total intracranial volume and age. Average processing time per subject was less than 4 minutes on a standard PC. The area under the receiver operator characteristic curve of the corrected HGMV for identification of MCI to probable AD converters within 12, 24, and 36 months was 0.78, 0.72, and 0.71, respectively. Thus, hippocampal volume computed with the fully-automated processing pipeline provides similar power for prediction of MCI to probable AD conversion as computationally more expensive methods. The whole processing pipeline has been made freely available as an SPM8 toolbox. It is easily set up and integrated into everyday clinical patient care. Show more

Keywords: ADNI, Alzheimer’s disease, atlas-based segmentation, fully automated, hippocampus volumetry, magnetic resonance imaging, mild cognitive impairment, prediction

DOI: 10.3233/JAD-142280

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 199-209, 2015