Journal of Alzheimer's Disease - Volume 34, issue 3

Authors: Olsson, Bob | Hertze, Joakim | Ohlsson, Mattias | Nägga, Katarina | Höglund, Kina | Basun, Hans | Annas, Peter | Lannfelt, Lars | Andreasen, Niels | Minthon, Lennart | Zetterberg, Henrik | Blennow, Kaj | Hansson, Oskar

Article Type: Research Article

Abstract: Heart fatty acid binding protein (HFABP) is expressed in the brain and is elevated in cerebrospinal fluid (CSF) from patients with several forms of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease with dementia, Lewy body dementia, vascular dementia (VaD), and Creutzfeldt-Jakob disease. However, whether HFABP in CSF is a stable biomarker or if it can help predict conversion from mild cognitive impairment (MCI) to AD or VaD has not been well studied. To address the role of HFABP in neurodegeneration, we analyzed CSF levels of HFABP in 96 AD patients and 65 controls and also in 170 patients …with MCI with an average follow up time of 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six month interval in between. HFABP levels in CSF were very stable over the six month period (r = 0.93, p < 0.001). Furthermore, the CSF levels of HFABP were significantly elevated in AD compared with controls after adjustments for age and gender (p < 0.001). They were also elevated in the patients with MCI that subsequently converted to AD or VaD compared with those that remained stable (p < 0.001 and p < 0.05, respectively). However, ROC curve analysis showed that HFABP had lesser predictive value in determining conversion from MCI to AD and VaD than Aβ42 , t-tau, and p-tau. In conclusion, HFABP seems to be a stable CSF biomarker that reflects neuronal cell death in several neurodegenerative disorders, including early stages of AD and VaD. Show more

Keywords: Alzheimer's disease, biomarker, cerebrospinal fluid, dementia, HFABP, vascular dementia

DOI: 10.3233/JAD-121384

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 673-679, 2013

Authors: Silva, Dina | Guerreiro, Manuela | Santana, Isabel | Rodrigues, Ana | Cardoso, Sandra | Maroco, João | de Mendonça, Alexandre

Article Type: Research Article

Abstract: The use of neuropsychological tests to detect cognitive decline in the initial phases of Alzheimer's disease (AD) has faced significant limitations, namely the fact that most cohort studies of conversion to dementia had relatively short follow-up periods. The aim of the present study is to assess the predictive value for future conversion to dementia of a comprehensive neuropsychological battery applied to a cohort of non-demented patients followed-up for 5 years. Participants (n = 250) were selected from the Cognitive Complaints Cohort (CCC) having cognitive complaints, assessment with a comprehensive neuropsychological battery, and a follow-up period of 5 years (unless patients …have converted to dementia earlier). During the follow-up period (2.6 ± 1.8 years for converters and 6.1 ± 2.1 years for non-converters), 162 patients (64.8%) progressed to dementia (mostly AD), and 88 (35.2%) did not. A Linear Discriminant Analysis (LDA) model constituted by Digit Span backward, Semantic Fluency, Logical Memory (immediate recall), and Forgetting Index significantly discriminated converters from non-converters (λ Wilks = 0.64; χ2 (4) = 81.95; p < 0.001; RCanonical = 0.60). Logical Memory (immediate recall) was the strongest predictor with a standardized canonical discriminant function coefficient of 0.70. The LDA classificatory model showed good sensitivity, specificity and accuracy values (78.8%, 79.9% and 78.6%, respectively) of the neuropsychological tests to predict long-term conversion to dementia. The present results show that it is possible to predict, on the basis of the initial clinical and neuropsychological evaluation, whether non-demented patients with cognitive complaints will probably convert to dementia, or remain stable, at a reasonably long and clinically relevant term. Show more

Keywords: Alzheimer's disease, cognitive markers, cohort study, dementia, executive functions, long-term follow-up, neuropsychological tests, predictive value, verbal memory

DOI: 10.3233/JAD-122098

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 681-689, 2013

Authors: Choi, Jennifer H.K. | Kaur, Gurjinder | Mazzella, Matthew J. | Morales-Corraliza, Jose | Levy, Efrat | Mathews, Paul M.

Article Type: Research Article

Abstract: Early endosomal changes, a prominent pathology in neurons early in Alzheimer's disease, also occur in neurons and peripheral tissues in Down syndrome. While in Down syndrome models increased amyloid-β protein precursor (AβPP) expression is known to be a necessary contributor on the trisomic background to this early endosomal pathology, increased AβPP alone has yet to be shown to be sufficient to drive early endosomal alterations in neurons. Comparing two AβPP transgenic mouse models, one that contains the AβPP Swedish K670N/M671L double mutation at the β-cleavage site (APP23) and one that has the AβPP London V717I mutation near the γ-cleavage site …(APPLd2), we show significantly altered early endosome morphology in fronto-parietal neurons as well as enlargement of early endosomes in basal forebrain cholinergic neurons of the medial septal nucleus in the APP23 model, which has the higher levels of AβPP β-C-terminal fragment (βCTF) accumulation. Early endosomal changes correlate with a marked loss of the cholinergic population, which is consistent with the known dependence of the large projection cholinergic cells on endosome-mediated retrograde neurotrophic transport. Our findings support the idea that increased expression of AβPP and AβPP metabolites in neurons is sufficient to drive early endosomal abnormalities in vivo, and that disruption of the endocytic system is likely to contribute to basal forebrain cholinergic vulnerability. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, cholinergic neurons, endocytosis, endosomes, septal nuclei

DOI: 10.3233/JAD-122143

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 691-700, 2013

Authors: O'Bryant, Sid E. | Johnson, Leigh | Edwards, Melissa | Soares, Holly | Devous, Michael D. | Ross, Sarah | Rohlfing, Geoffrey | Hall, James | for the Texas Alzheimer's Research & Care Consortium

Article Type: Research Article

Abstract: Background: The aim of this study is to evaluate the link between C-reactive protein (CRP) and Alzheimer’s disease (AD) and mild cognitive impairment (MCI) among Mexican Americans. Methods: Non-fasting serum CRP levels, Mini-Mental State Examination scores, and Clinical Dementia Rating scale (CDR) scores were analyzed from 1,066 participants (Mexican American n = 471; non-Hispanic n = 595) of the Texas Alzheimer’s Research & Care Consortium. Results: Among the total cohort, CRP levels among AD cases were significantly decreased as compared to normal controls (p < 0.001) and MCI cases (p = 0.002). CRP levels among MCI cases …were decreased relative to controls (p = 0.03). Among Mexican American and non-Hispanic AD cases, CRP levels were significantly decreased among AD cases as compared to controls. CRP levels were only associated with disease severity (CDR scores) among non-Hispanics (p = 0.03) AD cases. Conclusions: These results show that while CRP levels are decreased among Mexican American AD cases, CRP does not appear to be related to clinical variables as it is among non-Hispanic whites. Show more

Keywords: Alzheimer's disease, C-reactive protein, Mexican American, neuropsychology

DOI: 10.3233/JAD-122071

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 701-706, 2013

Authors: Babiloni, Claudio | Vecchio, Fabrizio | Del Percio, Claudio | Montagnese, Sara | Schiff, Sami | Lizio, Roberta | Chini, Giorgia | Serviddio, Gaetano | Marzano, Nicola | Soricelli, Andrea | Frisoni, Giovanni B. | Rossini, Paolo M. | Amodio, Piero

Article Type: Research Article

Abstract: Patients suffering from prodromal (i.e., amnestic mild cognitive impairment, aMCI) and overt Alzheimer's disease (AD) show abnormal cortical sources of resting state electroencephalographic (EEG) rhythms. Here we tested the hypothesis that these sources show extensive abnormalities in liver cirrhosis (LC) patients with a cognitive impairment due to covert and diffuse hepatic encephalopathy (CHE). EEG activity was recorded in 64 LC (including 21 CHE), 21 aMCI, 21 AD, and 21 cognitively intact (Nold) subjects. EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), and beta 2 (20–30 …Hz). EEG cortical sources were estimated by LORETA. Widespread sources of theta (all but frontal), alpha 1 (all but occipital), and alpha 2 (parietal, temporal) rhythms were higher in amplitude in all LC patients than in the Nold subjects. In these LC patients, the activity of central, parietal, and temporal theta sources correlated negatively, and parietal and temporal alpha 2 sources correlated positively with an index of global cognitive status. Finally, widespread theta (all but frontal) and alpha 1 (all but occipital) sources showed higher activity in the sub-group of LC patients with CHE than in the patients with aMCI or AD. These results unveiled the larger spatial-frequency abnormalities of the resting state EEG sources in the CHE compared to the AD condition. Show more

Keywords: Alzheimer's disease, covert hepatic encephalopathy, electroencephalography, hepatic encephalopathy, liver cirrhosis, low resolution brain electromagnetic tomography, mild cognitive impairment, minimal hepatic encephalopathy

DOI: 10.3233/JAD-121807

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 707-725, 2013

Authors: Kim, Bhumsoo | Backus, Carey | Oh, SangSu | Feldman, Eva L.

Article Type: Research Article

Abstract: Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer's disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. In parallel, AD patients have a higher than normal tendency to develop type 2 diabetes or impaired fasting glucose. Tau is the major component of neurofibrillary tangles, one of the hallmarks of AD pathology. The current study examined the effect of hyperglycemia on tau modification. Glucose treatment of rat embryonic cortical neurons results in concentration-dependent apoptosis and caspase-3 activation. These changes are well correlated with glucose time- and concentration-dependent tau cleavage. …Aβ treatment induces tau cleavage and when added together with glucose, there is an additive effect on caspase activation, apoptosis, and tau cleavage. Tau cleavage is partially blocked by the caspase inhibitor, ZVAD. Cleaved tau displays a punctate staining along the neurites and colocalizes with cleaved caspase-3 in the cytoplasm. Both type 1 and type 2 diabetic mice display increased tau phosphorylation in the brain. In agreement with the effects of glucose on tau modifications in vitro, there is increased tau cleavage in the brains of ob/ob mice; however, tau cleavage is not observed in type 1 diabetic mouse brains. Our study demonstrates that hyperglycemia is one of major factors that induce tau modification in both in vitro and in vivo models of diabetes. We speculate that tau cleavage in diabetic conditions (especially in type 2 diabetes) may be a key link for the increased incidence of AD in diabetic patients. Show more

Keywords: Alzheimer's disease, diabetes, hyperglycemia, tau

DOI: 10.3233/JAD-121669

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 727-739, 2013

Authors: Blautzik, Janusch | Keeser, Daniel | Berman, Albert | Paolini, Marco | Kirsch, Valerie | Mueller, Sophia | Coates, Ute | Reiser, Maximilian | Teipel, Stefan J. | Meindl, Thomas

Article Type: Research Article

Abstract: The investigation of cerebral resting-state networks (RSNs) by functional magnetic resonance imaging (fMRI) is a promising tool for the early diagnosis and follow-up of neuropsychiatric and neurodegenerative disorders like Alzheimer's disease (AD). In this context, the determination of inter-session reliability of these networks is crucial. However, data on network reliability in healthy elderly subjects is rare and does not exist for patients with amnestic mild cognitive impairment (aMCI), a prodromal stage of AD. Therefore, the aim of this study was to investigate the long-term test-retest reliability of RSNs in both groups. Twelve healthy controls (HC) and 13 aMCI patients underwent …resting-state fMRI and neuropsychological testing (CERAD test battery) twice, at baseline and after 13–16 months. Resting-state fMRI data was decomposed into independent components using independent component analysis. Inter-session test-retest reliability of the resulting RSNs was determined by calculating voxel-wise intra-class correlation coefficients. Overall test-retest reliability of corresponding RSNs was moderate to high in both groups, but significantly higher in the HC group compared to the aMCI group (p < 0.001), while the cognitive performance within the CERAD test battery remained stable over time in either group. Most reliable RSNs derived from the HC group and were associated with sensory and motor as well as higher order cognitive and the default-mode function. Particularly low reliability was found in basal frontal regions, which are known to be prone to susceptibility-induced noise. We conclude that stable RSNs may represent healthy aging, whereas decreased RSN reliability may indicate progressive neuro-functional alterations before the actual manifestation of clinical symptoms. Show more

Keywords: Default-mode network, functional magnetic resonance imaging, independent component analysis, intra-class correlation coefficient, mild cognitive impairment, resting-state networks, test-retest reliability

DOI: 10.3233/JAD-111970

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 741-754, 2013

Authors: Li, Xian-Hui | Xin, Xin | Wang, Yan | Wu, Jian-zhao | Jin, Zhen-dong | Ma, Li-na | Nie, Chun-jie | Xiao, Xiao | Hu, Yan | Jin, Man-wen

Article Type: Research Article

Abstract: Diabetic patients have a signifiantly higher risk of developing all forms of dementia. Pentamethylquercetin (PMQ) has been proven to have potential as an anti-diabetic agent. Nevertheless, whether PMQ can improve diabetes-induced cognitive dysfunction has not been investigated. To address this, we evaluated the effectiveness and underlying mechanisms of PMQ for ameliorating diabetes-related cognitive dysfunction in vivo and in vitro. Our results showed that Goto-Kakizaki (GK) rats displayed impairment in their learning abilities and memory capabilities. Furthermore, GK rats reflected cognitive dysfunction in proportion to the intensity of insulin resistance index. In addition, dendritic spine density and the % cell viability …significantly decreased in hippocampus neurons. High glucose conditions induced hippocampal neurons damage, inflicted dendritic spine dysontogenesis, and reduced Akt/cAMP response element-binding protein activation. Treatment with PMQ in GK rats significantly ameliorated cognitive deficits and neuronal damage and increased dendritic spine density, at least in part, by improving insulin resistance and metabolic disorders. Furthermore, PMQ significantly activated the Akt/cAMP response element-binding protein pathway and increased the expression of memory-related proteins in the downstream part of the Akt/cAMP response element-binding protein pathway, such as synaptophysin and glutamate receptor 1. In addition, PMQ inhibited high glucose-induced cellular toxicity. LY294002 appeared to partly inhibit PMQ-mediated protective effects in hippocampal neurons. The results suggest that insulin resistance could predominantly reduce Akt/cAMP response element-binding protein activation in the brain, which is associated with a higher risk of cognitive dysfunction. PMQ could provide a new potential option for the prevention of cognitive dysfunction in diabetes. Show more

Keywords: Akt/cAMP response element-binding protein pathway, cognitive deficits, dendrite, diabetes, pentamethylquercetin

DOI: 10.3233/JAD-122017

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 755-767, 2013

Authors: Espinosa, Ana | Alegret, Montserrat | Valero, Sergi | Vinyes-Junqué, Georgina | Hernández, Isabel | Mauleón, Ana | Rosende-Roca, Maitée | Ruiz, Agustín | López, Oscar | Tárraga, Lluís | Boada, Mercè

Article Type: Research Article

Abstract: The most recent studies about mild cognitive impairment (MCI) are focused on the search for factors that make patients more vulnerable to conversion to dementia, mainly Alzheimer's disease (AD). The aim of this study was to determine which neuropsychological test performances, including episodic memory profiles, and genetic risk factors (APOE ε4) better predict early conversion to dementia among the four MCI subtypes. Data from 550 MCI patients were analyzed for the purpose of this study and were classified according to Petersen's criteria (2004), and also taking into account the absence (probable MCI) or presence (possible MCI) of comorbidities that could …explain cognitive deficits. MCI cases were divided into Probable amnestic (Pr-aMCI) (n = 115), probable non-amnestic (Pr-naMCI) (n = 37), possible amnestic (Pss-aMCI) (n = 234), and possible non-amnestic (Pss-naMCI) (n = 164), single or multiple domain. In the whole MCI sample, regression analysis showed that low performances on Orientation, Verbal Delayed Recall of the Word List Learning test from WMS-III, and Luria's Clock test were associated with conversion to dementia, independently of APOE ε4 allele. Cox proportional-hazards showed that the Probable MCI subtype, presence of storage memory impairment, multiple domain condition, and presence of at least one ε4 allele increased the risk of conversion to dementia. Multivariate survival and Kapplan-Meier analyses showed that the Pr-aMCI with storage memory impairment had the most and closest risk of conversion to dementia. In conclusion, the Pr-aMCI subset of patients had 8.5 times more risk of converting to dementia than the Pss-naMCI group, who displayed the slowest conversion rate to dementia. Show more

Keywords: Amnestic, cognition, dementia conversion, genetics, mild cognitive impairment, risk factors

DOI: 10.3233/JAD-122002

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 769-780, 2013

Authors: Scullion, Gillian A. | Hewitt, Katherine N. | Pardon, Marie-Christine

Article Type: Research Article

Abstract: A lifestyle rich in physical and mental activities protects against Alzheimer's disease (AD) but the underlying mechanisms are unclear. We have proposed that this is mediated by a stress response and have shown that repeated exposure to novelty stress, which induces physical and exploratory activities, delays the progression of AD-like pathology in the TASTPM mouse model. Here, we aimed to establish the role played by corticotrophin-releasing factor receptor 1 (CRFR1), a major component of the stress axis, in TASTPM's behavioral and neuroendocrine responses to novelty and related protective effects. We show that the stress response of TASTPM mice is altered …with reduced CRFR1-mediated neuroendocrine and behavioral responses to novelty and a distinct profile of behavioral responses. Repeated novelty-induced CRFR1 activation, however, mediated the improved contextual fear memory and extinction performance of TASTPM mice and increased hippocampal and fronto-cortical levels of synaptophysin, a marker of synaptic density, and fronto-cortical levels of the post-synaptic marker PSD95. The N-methyl-D-aspartate receptor (NMDAR) is the major receptor for synaptic plasticity underlying learning and memory. Although novelty-induced NMDAR activation contributed to enhancement of fear memory and synaptophysin levels, antagonism of CRFR1 and NMDAR prevented the novelty-induced increase in hippocampal synaptophysin levels but reversed the other effects of CRFR1 inactivation, i.e., the enhancement of contextual fear extinction and fronto-cortical synaptophysin and PSD95 levels. These findings suggest a novel mechanism whereby a stimulating environment can delay AD symptoms through CRFR1 activation, facilitating NMDAR-mediated synaptic plasticity and synaptogenesis in a region-dependent manner, either directly, or indirectly, by modulating PSD95. Show more

Keywords: Active lifestyle, Alzheimer's disease, corticotrophin-releasing factor, genetic mouse model, learning and memory, synaptogenesis

DOI: 10.3233/JAD-122164

Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 781-793, 2013