Journal of Alzheimer's Disease - Volume 22, issue 4

Authors: Babiloni, Claudio | Lizio, Roberta | Vecchio, Fabrizio | Frisoni, Giovanni B. | Pievani, Michela | Geroldi, Cristina | Claudia, Fracassi | Ferri, Raffaele | Lanuzza, Bartolo | Rossini, Paolo M.

Article Type: Research Article

Abstract: Cortical sources of resting eyes-closed alpha rhythms are typically abnormal in mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects. Here we tested the hypothesis of a progressive impairment of cortical alpha reactivity to eye-opening across amnesic MCI and mild AD subjects, reflecting another aspect of the impairment of cortical neural synchronization. Resting electroencephalography (EEG) data were recorded in 36 normal elderly subjects (Nold), 91 amnesic MCI, and 31 mild AD subjects during eyes-closed and -open conditions. EEG sources were estimated by LORETA software. In the eye-closed condition, posterior alpha 1 (8–10.5 Hz) sources were lower in MCI and AD …than Nold subjects. The opposite was true for occipital delta sources (2–4 Hz). Reactivity to the eyes-open condition showed posterior alpha 1 and alpha 2 (10.5–13 Hz) sources was high in the Nold, intermediate in the MCI, and low in the AD subjects. Furthermore, occipital alpha 1 reactivity across MCI and AD subjects was correlated to the cognitive impairment as revealed by Mini-Mental State Examination score. In conclusion, at least at group level, the continuum across amnesic MCI and mild AD status is related to an impaired reactivity of cortical neuronal synchronization to eyes opening at alpha rhythms. Show more

Keywords: Alzheimer's disease, amnesic mild cognitive impairment, delta, theta, and alpha rhythms, electroencephalography, eyes-closed resting state, eyes-open resting state, low resolution brain electromagnetic tomography (LORETA)

DOI: 10.3233/JAD-2010-100798

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1047-1064, 2010

Authors: Samaranch, Lluís | Cervantes, Sebastián | Barabash, Ana | Alonso, Alvaro | Cabranes, José Antonio | Lamet, Isabel | Ancín, Inés | Lorenzo, Elena | Martínez-Lage, Pablo | Marcos, Alberto | Clarimón, Jordi | Alcolea, Daniel | Lleó, Alberto | Blesa, Rafael | Gómez-Isla, Teresa | Pastor, Pau

Article Type: Research Article

Abstract: Microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) are involved in the pathogenic mechanisms of Alzheimer's disease (AD). We prospectively followed three longitudinal independent samples (total n = 319) with amnestic mild cognitive impairment (MCI) and analyzed whether MAPT H1/H2 haplotypes and APOE ε4 polymorphisms accelerated the rate of progression from MCI to dementia. At the end of the study, 172 subjects remained cognitively stable, whereas 147 progressed to dementia. APOE ε4 and MAPT H1/H1 were independently associated with an increased rate of progression to dementia in the combined sample. Cox regression models of the combined MCI sample showed that …MAPT H1/H1 carriers had an increased rate of progression to dementia compared with non carriers (Hazard Ratio = 1.45; 95% CI = 1.04–2.02; p = 0.028) and time-to-progression was shortened by 1.37 years. APOE ε4 allele also accelerated progression to dementia (Hazard Ratio = 1.47; 95% CI = 1.06–2.04; p = 0.020) and reduced the time-to-progression by 0.87 years. Additionally, MAPT H1/H1 genotype and APOE ε4 allele had an additive effect in progression to dementia, increasing progression rate to dementia (Hazard Ratio = 2.24, 95% CI = 1.40–3.58; p = 0.001) and shortening time-to-progression to dementia by 2.92 years. Similar results were obtained when only considering progression to AD-type dementia. Our results suggest that both MAPT H1/H1 genotype and APOE ε4 allele lead to a more rapid progression to dementia among MCI subjects, probably mediating an increased rate of amyloid-β and tau brain deposition. Show more

Keywords: Alzheimer's disease, APOE, interaction, genetics, microtubule-associated tau protein, MAPT, mild cognitive impairment

DOI: 10.3233/JAD-2010-101011

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1065-1071, 2010

Authors: Mulder, Sandra D. | Hack, C. Erik | van der Flier, Wiesje M. | Scheltens, Philip | Blankenstein, Marinus A. | Veerhuis, Robert

Article Type: Research Article

Abstract: Serum amyloid P (SAP) and C-reactive protein (CRP) are proteins involved in innate immunity. The expression of SAP and CRP is increased in Alzheimer's disease (AD) brain tissue, compared to healthy controls. Although both proteins are found in cerebrospinal fluid (CSF), their origin is unclear. We investigated if increased local production of SAP and CRP in AD brain results in higher levels in CSF with the use of index values. To study this, SAP, CRP, and albumin levels were determined in CSF and serum samples of 30 control (65 ± 11 years; 57% female) and 140 AD subjects (65 ± …9 years; 53% female). To correct for inter-individual differences in protein diffusion from blood to CSF, quotients (Q = CSF/serum) of SAP, CRP, and albumin and index values (Qprotein /Qalb ) were calculated. The results showed no significant differences in SAP and CRP index values between control and AD subjects, although eight percent of individual AD patients showed evidence of intrathecal SAP or CRP production using the Reiber hyperbolic model. Interestingly, the SAP index value was much lower than expected, based on its molecular size. In conclusion, these data suggest that local production of SAP and CRP in the AD brain does not substantially contribute to the CSF levels. Show more

Keywords: Alzheimer's disease, C-reactive protein, index value, serum amyloid p

DOI: 10.3233/JAD-2010-100888

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1073-1079, 2010

Authors: Bahar-Fuchs, Alex | Chételat, Gael | Villemagne, Victor L. | Moss, Simon | Pike, Kerryn | Masters, Colin L. | Rowe, Christopher | Savage, Greg

Article Type: Research Article

Abstract: Olfactory deficits and increased amyloid-β (Aβ) burden are observed in people with amnestic mild cognitive impairment (aMCI); both factors may be predictive of Alzheimer's disease (AD). We explored whether olfactory identification is related to in vivo measures of Aβ burden using Pittsburgh Compound B (PiB) PET. Nineteen control, 24 aMCI, and 20 AD participants completed an olfactory identification task and underwent PiB PET scanning. Control participants performed better on olfactory identification and showed lower PiB binding than aMCI patients. There was a significant correlation between both factors when pooling all groups together but not when considering each group separately. In …addition, the olfactory identification score did not differ between aMCI participants who were PiB-positive and those who were PiB-negative. We conclude that AD-related olfactory identification deficits are not directly related to Aβ burden. Show more

Keywords: Alzheimer's disease, amyloid-β, diagnosis, mild cognitive impairment, olfaction, PET imaging, Pittsburgh Compound B

DOI: 10.3233/JAD-2010-100696

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1081-1087, 2010

Authors: Paajanen, Teemu | Hänninen, Tuomo | Tunnard, Catherine | Mecocci, Patrizia | Sobow, Tomasz | Tsolaki, Magda | Vellas, Bruno | Lovestone, Simon | Soininen, Hilkka | for the AddNeuroMed Consortium,

Article Type: Research Article

Abstract: An important focus in Alzheimer's disease (AD) research is the development of methods for early diagnosis. Despite progress with some other biomarkers, sensitive and specific neuropsychological measures for identifying subjects in the prodromal phase of AD remain the most promising early diagnostic tool. We evaluated the value of the composite score for the Consortium to Establish a Registry for Alzheimer's disease Neuropsychological Battery (CERAD-NB) in Europeans with mild cognitive impairment (MCI) and in control populations. Baseline clinical data were analyzed from 223 healthy elderly and 224 subjects with MCI from the prospective AddNeuroMed study carried out in Finland, France, Greece, …Italy, Poland, and the United Kingdom. The total score for CERAD-NB was calculated by the subtest addition method. The CERAD total score, adjusted for age, gender, education, and country, clearly differentiated the control and MCI groups (p < 0.001). The optimal between-groups cut-off point for the CERAD total score derived from ROC analysis yielded 81.5% sensitivity and 75.4% specificity (AUC = 0.848, p < 0.001). The CERAD total score was superior to the Mini-Mental Status Examination, or any single CERAD subtest in discriminating between the control and MCI groups. While the overall level of the CERAD total score varied between the different countries, it remained accurate in differentiating controls and MCI subjects within each country. We conclude that the CERAD total score is an accurate measure for detecting mild cognitive impairment, but implementing specific cut-off points needs to be based upon country specific normative data. Show more

Keywords: Alzheimer's disease, cognition, memory, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-2010-100459

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1089-1097, 2010

Authors: Thambisetty, Madhav | Tripaldi, Romina | Riddoch-Contreras, Joanna | Hye, Abdul | An, Yang | Campbell, James | Sojkova, Jitka | Kinsey, Anna | Lynham, Steven | Zhou, Yun | Ferrucci, Luigi | Wong, Dean F. | Lovestone, Simon | Resnick, Susan M.

Article Type: Research Article

Abstract: Blood-based markers reflecting core pathological features of Alzheimer's disease (AD) in pre-symptomatic individuals are likely to accelerate the development of disease-modifying treatments. Our aim was to discover plasma proteins associated with brain amyloid-β (Aβ) burden in non-demented older individuals. We performed discovery-phase experiments using two dimensional gel electrophoresis (2DGE) and mass spectrometry-based proteomic analysis of plasma in combination with 11 C-PiB PET imaging of the brain in samples collected 10 years prior to the PET scans. Confirmatory studies used ELISA assays in a separate set of blood samples obtained within a year of the PET scans. We observed that a …panel of 18 2DGE plasma protein spots effectively discriminated between individuals with high and low brain Aβ. Mass spectrometry identified these proteins, many of which have established roles in Aβ clearance, including a strong signal from apolipoprotein-E (ApoE). In validation-phase studies, we observed a strong association between plasma ApoE concentration and Aβ burden in the medial temporal lobe. Targeted voxel-based analysis localized this association to the hippocampus and entorhinal cortex. APOE ε4 carriers also showed greater Aβ levels in several brain regions relative to ε4 non-carriers. These results suggest that both peripheral concentration of ApoE protein and APOE genotype are related to early neuropathological changes in brain regions vulnerable to AD pathology even in the non-demented elderly. Our strategy combining proteomics with in vivo brain amyloid imaging holds promise for the discovery of biologically relevant peripheral markers in those at risk for AD. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarker, brain, plasma, proteomics

DOI: 10.3233/JAD-2010-101350

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1099-1109, 2010

Authors: Coulson, David T.R. | Beyer, Nancy | Quinn, Joe G. | Brockbank, Simon | Hellemans, Jan | Irvine, G. Brent | Ravid, Rivka | Johnston, Janet A.

Article Type: Research Article

Abstract: β-site AβPP cleaving enzyme 1 (BACE1) catalyses the rate-limiting step for production of amyloid-β (Aβ) peptides, involved in the pathological cascade underlying Alzheimer's disease (AD). Elevated BACE1 protein levels and activity have been reported in AD postmortem brains. Our study explored whether this was due to elevated BACE1 mRNA expression. RNA was prepared from five brain regions in three study groups: controls, individuals with AD, and another neurodegenerative disease group affected by either Parkinson's disease (PD) or dementia with Lewy bodies (DLB). BACE1 mRNA levels were measured using quantitative realtime PCR (qPCR) and analyzed by qbasePLUS using validated stably-expressed …reference genes. Expression of glial and neuronal markers (glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE), respectively) were also analyzed to quantify the changing activities of these cell populations in the tissue. BACE1 mRNA levels were significantly elevated in medial temporal and superior parietal gyri, compared to the PD/DLB and/or control groups. Superior frontal gryus BACE1 mRNA levels were significantly increased in the PD/DLB group, compared to AD and control groups. For the AD group, BACE1 mRNA changes were analyzed in the context of the reduced NSE mRNA, and strongly increased GFAP mRNA levels apparent as AD progressed (indicated by Braak stage). This analysis suggested that increased BACE1 mRNA expression in remaining neuronal cells may contribute to the increased BACE1 protein levels and activity found in brain regions affected by AD. Show more

Keywords: Amyloid-β protein precursor, Braak staging, gene expression, Lewy body disease, Parkinson's disease, protease, qPCR, reference gene, reverse transcriptase polymerase chain reaction

DOI: 10.3233/JAD-2010-101254

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1111-1122, 2010

Authors: Gabryelewicz, Tomasz | Masellis, Mario | Berdynski, Mariusz | Bilbao, Juan M. | Rogaeva, Ekaterina | St. George-Hyslop, Peter | Barczak, Anna | Czyzewski, Krzysztof | Barcikowska, Maria | Wszolek, Zbigniew | Black, Sandra E. | Zekanowski, Cezary

Article Type: Research Article

Abstract: Frontotemporal dementia (FTD) is one of the commonest forms of early-onset dementia, accounting for up to 20% of all dementia patients. Recently, it has been shown that mutations in progranulin gene (PGRN) cause many familial cases of FTD. Members of a family affected by FTD spectrum disorders were ascertained in Poland and Canada. Clinical, radiological, molecular, genetic, and pathological studies were performed. A sequencing analysis of PGRN exons 1–13 was performed in the proband. Genotyping of the identified PGRN mutation and pathological analysis was carried out in the proband's brother. The onset of symptoms of FTD in the proband included …bradykinesia, apathy, and somnolence followed by changes in personality, cognitive deficits, and psychotic features. The proband's clinical diagnosis was FTD and parkinsonism (FTDP). DNA sequence analysis of PGRN revealed a novel, heterozygous mutation in exon 11 (g.2988_2989delCA, P439_R440fsX6). The mutation introduced a premature stop codon at position 444. The proband's brother with the same mutation had a different course first presenting as progressive non-fluent aphasia, and later evolving symptoms of behavioral variant of FTD. He also developed parkinsonism late in the disease course evolving into corticobasal syndrome. Pathological analysis in the brother revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/TDP-43 positive pathology. The novel PGRN mutation is a disease-causing mutation and is associated with substantial intra-familial clinical heterogeneity. Although presenting features were different, rapid and substantial deterioration in the disease course was observed in both family members. Show more

Keywords: Corticobasal syndrome, frontotemporal dementia, haploinsufficiency, parkinsonism, progranulin mutation, progressive non-fluent aphasia

DOI: 10.3233/JAD-2010-101413

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1123-1133, 2010

Authors: Lichtenstein, Mathieu P. | Carriba, Paulina | Baltrons, María Antonia | Wojciak-Stothard, Beata | Peterson, Jeffrey R. | García, Agustina | Galea, Elena

Article Type: Research Article

Abstract: Profens like ibuprofen, R-flurbiprofen, or CHF5074 are being considered for the treatment of Alzheimer's disease because epidemiological data indicates that non-steroidal anti-inflammatory drugs are protective against neurodegeneration. Rho-GTPases are small G proteins, including RhoA, Cdc42, and Rac1, which control cytoskeleton dynamics. Because ibuprofen promotes axon growth via RhoA in neurons, we examined whether profens modulate astrocyte plasticity via Rho-GTPases. We report that ibuprofen (100–500 μM), R-flurbiprofen (100–500 μM), and CHF5074 (10–30 μM) caused a concentration-dependent stellation of astrocytes in primary cultures, associated with the reorganization of GFAP and actin filaments. The stellation was independent of COX2, α-, β- or γ-secretase …as judged by the lack of effect of inhibitors of these enzymes. RhoA, PAK, and Cdc42, but not Rac1, accounted for the profen-mediated stellation, as concluded from the joint analyses of activities and reversal experiments with adenoviral or pharmacological manipulations. Ibuprofen accelerated migration in a scratch-wound assay, while R-flurbiprofen had no effect and CHF5074 caused deceleration. Cell polarity regulation by Cdc42 and ERK1/2 may underlie the paradoxical effects of profens on migration. We conclude that profens regulate cytoskeleton dynamics in astrocytes via Rho-GTPases, PAK, and ERK1/2. Since migration is a hallmark of astrocyte response during inflammation we propose that, in addition to (or instead of) lowering amyloid-β42 via secretases, ibuprofen and its derivatives may prevent Alzheimer's disease instead of AD by modulating astrocyte reactivity through Rho-GTPase/PAK/ERK-dependent signaling. Show more

Keywords: Actin, Alzheimer's disease, astrocytes, Cdc42, CHF5074, ibuprofen, IPA3, NSAIDs, Rac1, RhoA, R-Flurbiprofen

DOI: 10.3233/JAD-2010-101332

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1135-1155, 2010

Authors: Garre-Olmo, Josep | López-Pousa, Secundino | Vilalta-Franch, Joan | de Gracia Blanco, Manuel | Vilarrasa, Antoni Bulbena

Article Type: Research Article

Abstract: Behavioral and psychological symptoms of dementia (BPSD) are frequently observed in Alzheimer's disease (AD) and affect more than 80% of patients over the course of AD. The goal of this study was to establish a model for grouping the symptoms of BPSD into clinical syndromes. Over a 24-month period, an observational study was conducted using a population of ambulatory patients with AD of mild to moderate severity. The Neuropsychiatric Inventory (NPI) was administered to the patients' caregivers every 6 months. BPSD were grouped using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) of the NPI scores of each assessment. …The sample population consisted of 491 patients (70.9% women) with an average age of 75.2 years (SD = 6.6). The five EFA suggested that there was a stable three-factor structure. According to the results of the EFA, three models of symptom grouping were adjusted using CFA methodology. The CFA model that satisfactorily grouped the NPI scores into three factors included a psychotic syndrome (hallucinations, delusions), an affective syndrome (depression, anxiety, irritability, agitation) and a behavior syndrome (euphoria, disinhibition, apathy, aberrant motor behavior). Based on our findings, we propose a model for grouping the BDSD in which there are core nuclear syndromes (psychotic and affective) as well as an unspecified behavior syndrome comprising satellite symptoms that may be related to the presence of the nuclear syndromes. Show more

Keywords: Alzheimer's disease, longitudinal study, mood disorders, neurobehavioral manifestations, psychotic disorders, statistical factor analysis, statistical model

DOI: 10.3233/JAD-2010-101212

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1157-1167, 2010