Journal of Alzheimer's Disease - Volume 36, issue 1

Authors: Faxén-Irving, Gerd | Freund-Levi, Yvonne | Eriksdotter-Jönhagen, Maria | Basun, Hans | Hjorth, Erik | Palmblad, Jan | Vedin, Inger | Cederholm, Tommy | Wahlund, Lars-Olof

Article Type: Research Article

Abstract: Transthyretin (TTR) binds amyloid-β (Aβ) and may reduce brain Aβ, a pathological feature in Alzheimer's disease (AD). N − 3 fatty acids (FA), docosahexaenoic (DHA), and eicosapentaenoic acid (EPA) may increase TTR transcription in rat hippocampus. We studied effects of n − 3 FA supplementation on TTR-levels in patients with AD. Outpatients were randomized to receive 1.7 g DHA and 0.6 g EPA (n − 3/n − 3 group) or placebo (placebo/n − 3 group) during 6 months. After 6 months, all patients received n − 3 FA for another 6 months. TTR and FA were measured in plasma in …all subjects, whereas TTR in cerebrospinal fluid (CSF) was measured in a subgroup. The study was completed by 89 patients in the n − 3/n − 3 group (75 y, 57% w) and 85 in the placebo/n − 3 group (75 y, 46% w). Baseline plasma-TTR was within normal range in both groups. After 6 months, plasma-TTR decreased in the placebo/n − 3 group (p < 0.001 within and p < 0.015 between the groups). No changes were observed in CSF TTR. From 6 to 12 months when both groups were supplemented, plasma-TTR increased significantly in both groups. Repeated measures ANOVA indicated an increase in TTR over time (p = 0.04) in those receiving n − 3 FA for 12 months. By linear regression analyses, n − 3 FA treatment was independently associated with increased plasma-TTR at 6 months (β = −0.172, p = 0.028). Thus, n − 3 FA treatment appeared to increase plasma-TTR in patients with AD. Since TTR may influence Aβ deposition in the brain, the results warrant further exploration. Show more

Keywords: Alzheimer's disease, dementia, fatty acids, transthyretin

DOI: 10.3233/JAD-121828

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 1-6, 2013

Authors: Semar, Sandra | Klotz, Markus | Letiembre, Maryse | Van Ginneken, Chris | Braun, Anne | Jost, Viktor | Bischof, Michael | Lammers, Wim J. | Liu, Yang | Fassbender, Klaus | Wyss-Coray, Tony | Kirchhoff, Frank | Schäfer, Karl-Herbert

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), fatal neuronal cell loss occurs long before relevant evidence can lead to a reliable diagnosis. If characteristic pathological alterations take place in the enteric nervous system (ENS), it could be one of the most promising targets for an early diagnosis, using submucosal biopsies from the gut. We therefore investigated time- and spatial-dependent changes in an amyloid-β protein precursor (AβPP) overexpressing transgenic mouse model to examine early changes within the ENS. Wholemount preparations and paraffin sections were analyzed for the expression of neuronal, glial, and innate immunity markers. Isolated myenteric networks were screened for differences in overall …protein expression, and a motility analysis delivered functional data. The level of AβPP in the gut was significantly higher in the AD mouse model than in wild-type mice and also higher in the gut than in the brain at all ages investigated. The transcriptional level of Nestin, GFAP, and TLR4 increased with age with a peak at 3 months. At the protein level, human amyloid-β was located in myenteric neurons. Myenteric networks showed a reduction of the neuronal density in AβPP compared to wild-type mice, which was functionally relevant as revealed by motility analysis. The ENS undergoes significant changes during the early onset of AβPP expression in AD mouse models that appear before those seen in the brain as demonstrated in this study. Thus, there is a chance of determining similar alterations in the human gut of AD patients, which could be used to develop early diagnostic approaches. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, enteric nervous system, potential biomarker

DOI: 10.3233/JAD-120511

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 7-20, 2013

Authors: George, Roshni C. | Lew, John | Graves, Donald J.

Article Type: Research Article

Abstract: Abnormal modifications in tau such as hyperphosphorylation, oxidation, and glycation interfere with its interaction with microtubules leading to its dissociation and self-aggregation into neurofibrillary tangles, a hallmark of Alzheimer's disease (AD). Previously we reported that an aqueous extract of cinnamon has the ability to inhibit tau aggregation in vitro and can even induce dissociation of tangles isolated from AD brain. In the present study, we carried out investigations with cinnamaldehyde (CA) and epicatechin (EC), two components of active cinnamon extract. We found that CA and the oxidized form of EC (ECox ) inhibited tau aggregation in vitro and the activity …was due to their interaction with the two cysteine residues in tau. Mass spectrometry of a synthetic peptide, SKCGS, representing the actual tau sequence, identified the thiol as reacting with CA and ECox . Use of a cysteine double mutant of tau showed the necessity of cysteine for aggregation inhibition by CA. The interaction of CA with tau cysteines was reversible and the presence of CA did not impair the biological function of tau in tubulin assembly in vitro. Further, these compounds protected tau from oxidation caused by the reactive oxygen species, H2 O2 , and prevented subsequent formation of high molecular weight species that are considered to stimulate tangle formation. Finally, we observed that EC can sequester highly reactive and toxic byproducts of oxidation such as acrolein. Our results suggest that small molecules that form a reversible interaction with cysteines have the potential to protect tau from abnormal modifications. Show more

Keywords: Aggregation, Alzheimer's disease, cinnamaldehyde, cysteine, epicatechin, hydrogen peroxide, reactive oxygen species, tau protein

DOI: 10.3233/JAD-122113

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 21-40, 2013

Authors: Chang, Jae Seung | Chi, Yeon Kyung | Han, Ji Won | Kim, Tae Hui | Youn, Jong Chul | Lee, Seok Bum | Park, Joon Hyuk | Lee, Jung Jae | Ha, Kyooseob | Kim, Ki Woong

Article Type: Research Article

Abstract: Decreased semantic memory has been suggested as an early sign in Alzheimer's disease (AD). This study aimed to investigate qualitative differences in semantic network between AD patients and healthy community-dwelling elderly controls. Category fluency test (animal) was administered to 416 AD patients and 339 controls. Mini-Mental State Examination was administered to evaluate global cognition. Patterns of semantic organization were compared between the two groups using hierarchical clustering (HC) and multidimensional scaling (MDS). In HC analysis, whereas a logically organized semantic structure was observed in the control group with an elaborate use of general knowledge, the semantic structure of the patient …group was not interpretable. In MDS mapping, two dimensions of domesticity and size were identified in the control group. The MDS map of AD patients showed mixed features of perception and emotion. Knowledge-based semantic associations may be impaired in AD patients, which can add an extra dimension to cognitive impairments in AD patients regardless of quantitative facets of cognitive dysfunction. Show more

Keywords: Alzheimer's disease, category fluency, hierarchical clustering, multidimensional scaling, semantic memory

DOI: 10.3233/JAD-122458

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 41-48, 2013

Authors: Padovani, Alessandro | Premi, Enrico | Pilotto, Andrea | Gazzina, Stefano | Cosseddu, Maura | Archetti, Silvana | Cancelli, Vanessa | Paghera, Barbara | Borroni, Barbara

Article Type: Research Article

Abstract: Background: Differential diagnosis between frontotemporal dementia (FTD) and Alzheimer’s disease (AD) is often challenging. Autopsy series have identified AD pathology in a consistent percentage of patients clinically diagnosed with frontotemporal dementia (FTD). It has been demonstrated that the levels of tau and Aβ 42 in cerebrospinal fluid (CSF) are a reliable marker for AD. Objective: To evaluate the presence of a CSF AD-like pattern in patients with FTD, and the related brain changes, to assess whether these patients had features resembling an AD pattern of hypoperfusion. Methods: Clinically-diagnosed non-monogenic FTD patients underwent an extensive neuropsychological …assessment, 99m Tc-ECD SPECT, and CSF analysis (tau and Aβ 42 levels). FTD AD-like and FTD non-AD-like patterns were identified, and neuropsychological and neuroimaging features compared. Results: CSF AD-like pattern was reported in 9 cases out of 43 (21%). FTD AD-like and non-AD-like patients did not differ in demographic characteristics, cognitive deficits, or behavioral changes. Both groups had greater hypoperfusion in frontotemporal lobes as compared to age-matched controls. When FTD AD-like patients were compared to the FTD non-AD-like group, the former had greater hypoperfusion in brain areas typically affected by AD, namely precuneus, temporal, and parietal areas. Conclusions: CSF AD-like profile in FTD is associated with brain abnormalities typically found in classical AD, confirming the usefulness of CSF testing. Detecting an ongoing AD pathological process in FTD has several implications for defining distinctive treatment approaches, guiding genetic screening, and helping in patient selection in future clinical trials in both FTLD and AD therapeutics. Show more

Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, frontotemporal dementia, SPECT, tau

DOI: 10.3233/JAD-121969

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 49-55, 2013

Authors: de Souza, Leonardo Cruz | Chupin, Marie | Bertoux, Maxime | Lehéricy, Stéphane | Dubois, Bruno | Lamari, Foudil | Le Ber, Isabelle | Bottlaender, Michel | Colliot, Olivier | Sarazin, Marie

Article Type: Research Article

Abstract: Background: Previous studies analyzed the ability of hippocampal volumes (HV) to differentiate Alzheimer’s disease (AD) from frontotemporal dementia (FTD). However, these studies did not include patients selected according to clinico-biological criteria, using pathophysiological biomarkers. Objective: To analyze the effectiveness of hippocampal volumetric measures to distinguish AD from behavioral variant FTD (bvFTD), using strict inclusion criteria based on clinical and pathophysiological markers. Methods: Seventy-two participants were included: 31 AD patients with predominant and progressive episodic memory deficits associated with typical AD cerebrospinal fluid (CSF) profile and/or positive amyloid imaging (PET with 11 C-labeled Pittsburgh Compound B [PiB]), …26 bvFTD patients diagnosed according to consensual clinical criteria and with no AD CSF profile, and 15 healthy controls without amyloid retention on PiB-PET exam. HV were segmented with an automated method and were normalized to total intracranial volume (nHV). Results: Significant reductions in HV were found in both AD and bvFTD patients compared with controls, but there were no significant difference between AD and bvFTD patients. Mean nHV distinguished normal controls from either AD or bvFTD with high sensitivity (80.6% and 76.9%, respectively) and specificity (93.3% for both), but it was inefficient in differentiating AD from bvFTD (9.7% specificity). There was no difference in the clinical and neuropsychological profiles according to HV in bvFTD and AD patients. Conclusions: When considered alone, measures of HV are not good markers to differentiate AD from bvFTD. Hippocampal sclerosis associated with FTD may explain the high degree of overlap in nHV between both groups. Show more

Keywords: Alzheimer's disease, frontotemporal dementia, volumetric MRI

DOI: 10.3233/JAD-122293

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 57-66, 2013

Authors: Molinuevo, Jose L. | Gispert, Juan Domingo | Dubois, Bruno | Heneka, Michael T. | Lleo, Alberto | Engelborghs, Sebastiaan | Pujol, Jesús | de Souza, Leonardo Cruz | Alcolea, Daniel | Jessen, Frank | Sarazin, Marie | Lamari, Foudil | Balasa, Mircea | Antonell, Anna | Rami, Lorena

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) show an acceptable diagnostic sensitivity and specificity; however, their interpretation and ease of use is far from optimal. Objective: To study and validate the diagnostic accuracy of an easy-to-use normalized CSF biomarker index, the AD-CSF-index, in different European populations. Methods: A total of 342 subjects, 103 healthy controls and 239 AD patients, from four European memory clinics were included. The AD-CSF-index was constructed from the addition of normalized values between the minimum and maximum of amyloid and tau protein levels. The diagnostic accuracy, receiver operating characteristic, and …regression analysis of the AD-CSF-index and other composite indices were evaluated in this study. Results: AD patients presented a significantly higher AD-CSF-index than healthy subjects (control = 0.5204; AD = 1.2272; p < 0.001). The AD-CSF-index obtained a sensitivity of 88.6% at 85% specificity and also showed a significantly higher diagnostic power (p < 0.05) than the individual CSF biomarkers and other studied indices. The performance of the AD-CSF-index was very similar between ELISA and MesoScale measurements. Cut-off values of approximately 0.75 provided the lowest achievable overall classification errors and a cut-off point of about 0.95 consistently provided specificities above 85%. Conclusion: The AD-CSF-index represents a novel approach, combining normalized CSF values, for the biological diagnosis of AD. The AD-CSF-index presents an optimal AUC with high sensitivity and specificity and seems to be a simple and intuitive way to interpret AD CSF biomarker results even from different analytical platforms. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, diagnostic accuracy, sensitivity, specificity

DOI: 10.3233/JAD-130203

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 67-77, 2013

Authors: Prins, Niels D. | van der Flier, Wiesje M. | Brashear, H. Robert | Knol, Dirk L. | van de Pol, Laura A. | Barkhof, Frederik | Scheltens, Philip

Article Type: Research Article

Abstract: We studied the predictive value of cognitive performance, vascular risk factors, apolipoprotein E (APOE) genotype, and structural brain changes on MRI, on progression to dementia in post hoc analyses of 426 placebo patients (mean age 71 years; 55% women) with mild cognitive impairment (MCI) who participated in a previously published large multi-center clinical trial (Gal-Int-11). The ADAS-cog/MCI test, the New York University Paragraph Recall Test, and the Digit Symbol Coding Test were available at baseline, as were vascular risk factors and APOE genotype. Medial temporal lobe atrophy (MTA), white matter hyperintensities (WMH) and lacunes were assessed on MRI. Over two …years of follow-up, 81 patients (19%) converted to dementia, while 345 patients (81%) remained stable. Results of Cox proportional-hazards regression analysis showed that higher age, worse cognitive test performance, presence of an APOE ε4 allele, and higher MTA scores on MRI increased the risk of progression to dementia in univariate analyses. Vascular risk factors, and WMH and lacunes on MRI, were not associated with progression to dementia. Lower performance on the ADAS-cog/MCI test (HR 1.08 per point increase; 95% CI 1.06–1.10) and Delayed recall test (HR 0.76 per point increase; 95% CI 0.68–0.85), as well as higher MTA scores on MRI (HR 1.33 per point increase; 95% CI 1.00–1.77) were independent predictors of progression to dementia in a step-wise Cox proportional-hazards model with age and gender forced into the model. We conclude that global cognitive function, episodic memory performance, and MTA on MRI independently predict progression to dementia in patients with MCI. Show more

Keywords: Alzheimer's disease, apolipoprotein E, brain infarction, clinical trial, dementia, hippocampus, leukoaraiosis, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-122233

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 79-85, 2013

Authors: Valenzuela, Michael J. | Leon, Irene | Suo, Chao | Piamba, Diana Martinez | Kochan, Nicole | Brodaty, Henry | Sachdev, Perminder

Article Type: Research Article

Abstract: Background: Cognitive lifestyle may be an important modifiable risk factor for dementia but has not yet been comprehensively studied in healthy elderly. Objective: To examine gender- and lifespan-related differences in cognitive lifestyle in a population-based cohort. Methods: 872 individuals from the second wave of the Sydney Memory and Ageing Study (MAS) cohort were invited to complete the Lifetime of Experiences Questionnaire (LEQ), a validated measure of cognitive lifestyle. Of 555 questionnaires returned (64%), 253 were excluded due to prior diagnosis of mild cognitive impairment, leaving n = 302 cognitively-intact elders (mean age 80.1 years, ±SD 4.7, …40.1% men). Results: Total LEQ was significantly higher in men (97.9 ± 20.0) than women (90.0 ± 24.5), resulting mainly from midlife LEQ differences. Men were more likely to have worked in managerial or professional jobs (73.8% versus 39.5% women), and twice as likely to have supervised large groups of workers. In late life, women were significantly more likely to be living alone (68.1% versus 25.4% men), but otherwise significantly more engaged in specific cognitive activities, including reading novels (72.3% versus 52.0% men) and incorporating volunteer work (31.9% versus 19.7% men) and socializing (59.0% versus 37.0% men) into their typical day. Over the adult lifespan, it was more common for men and women to transition between LEQ tertiles than remain the same. Conclusions: Cognitive lifestyle changes over the adult lifespan and exhibits a range of gender-based differences. While older women are more likely to be living alone they generally lead a more active current cognitive lifestyle. Show more

Keywords: Alzheimer's disease, dementia, epidemiology, lifestyle, prevention, protection

DOI: 10.3233/JAD-130143

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 87-97, 2013

Authors: Carvajal, Francisco J. | Zolezzi, Juan M. | Tapia-Rojas, Cheril | Godoy, Juan A. | Inestrosa, Nibaldo C.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle deposition, synaptic alterations, and oxidative injury. In AD patients, acetylcholinesterase (AChE) activity is low in most regions of the brain, but increased within and around amyloid plaques, where it accelerates the Aβ assembly into oligomers and fibrils, increasing its neurotoxicity. Tetrahydrohyperforin (THH), a semi-synthetic derivative of hyperforin, reduces tau phosphorylation and Aβ accumulation in AD mouse models. In the present study, we examined the effects of THH on Aβ-AChE complexes, α7-nicotinic acetylcholine receptors (α7-nAChR), 4-hydroxynonenal (4-HNE) adducts, caspase-3 activation, …and spatial memory in young AβPPSwe/PSEN1ΔE9 (AβPP/PS1) transgenic mice, in order to evaluate its potential preventive effects on the development of the disease. We report here that treatment with THH prevents the association of AChE to different types of amyloid plaques; partially restores the brain distribution of AChE molecular forms; increases α7-nAChR levels in the hippocampus of treated mice; decreases the amount of these receptors in amyloid plaques; and reduces the oxidative damage, evidenced by 4-HNE adduct formation and caspase-3 activation on AβPP/PS1 mice brain; demonstrating the neuroprotective properties of THH. Finally, we found that the acute treatment of hippocampal neurons with THH, in the presence of Aβ-AChE complexes, prevents 4-HNE adduct formation and caspase-3 activation. Our data support a therapeutic potential of THH for the treatment of AD. Show more

Keywords: AβPP/PS1 transgenic mice, acetylcholinesterase, α7-nAChR, Alzheimer's disease, Aβ-AChE interactions, caspase-3, 4-hydroxynonenal adducts, tetrahydrohyperforin

DOI: 10.3233/JAD-130230

Citation: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 99-118, 2013