Journal of Alzheimer s Disease

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

doi: 10.3233/JAD-2010-100798pmid: 20930306

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.

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

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

doi: 10.3233/JAD-2010-100888pmid: 20930309

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 (Q protein /Q alb ) 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.

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

doi: 10.3233/JAD-2010-100696pmid: 20930316

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.

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

doi: 10.3233/JAD-2010-100459pmid: 20930314

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.

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.

doi: 10.3233/JAD-2010-101350pmid: 20930274

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

doi: 10.3233/JAD-2010-101254pmid: 20930286

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 qbase PLUS 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.

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

doi: 10.3233/JAD-2010-101413pmid: 20930269

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.

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

doi: 10.3233/JAD-2010-101332pmid: 20930267

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-β 42 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.

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

doi: 10.3233/JAD-2010-101212pmid: 20930289

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.