Volume 24, Number 3, May 2011

Pages 409-413
Short Communication
Irene Piaceri, Silvia Bagnoli, Ersilia Lucenteforte, Michelangelo Mancuso, Andrea Tedde , Gabriele Siciliano, Silvia Piacentini, Laura Bracco, Sandro Sorbi, Benedetta Nacmias (Handling Associate Editor: Daniela Galimberti)
Implication of a Genetic Variant at PICALM in Alzheimer’s Disease Patients and Centenarians
Abstract: A common polymorphism (rs3851179) in the PICALM (phosphatidylinositol-binding clathrin assembly protein) gene has been recently associated with reduced risk of developing late-onset Alzheimer’s disease (LOAD). We analyzed the genotype and allele distributions of the PICALM polymorphism in 813 Italian subjects, including LOAD patients and centenarians. The segregation of the PICALM rs3851179 showed no statistically significant difference between LOAD cases and controls. The implication of a genetic variant at PICALM is confirmed for the first time, in centenarians, thus suggesting a possible role in longevity.

Pages 415-419
Short Communication
Livia Bernardi, Maria Anfossi, Maura Gallo, Silvana Geracitano, Rosanna Colao, Gianfranco Puccio, Sabrina AM Curcio, Francesca Frangipane, Maria Mirabelli, Alessandra Clodomiro, Raffaele Di Lorenzo, Nicoletta Smirne, Raffaele Maletta, David Iapaolo, Amalia C. Bruni(Handling Associate Editor: Daniela Galimberti)
PSEN1 and PRNP gene mutations co-occurrence makes onset very early in a family with FTD phenotype
Abstract: Prion protein (PRNP) gene mutations have recently been associated with clinical pictures resembling Frontotemporal dementia (FTD). We describe a novel seven extra-repeat insertional mutation in the PRNP gene in a family affected by early-onset autosomal dominant FTD previously reported as caused by a PSEN1 mutation in which there was inconsistency between clinical picture and genotype. Both mutations were pathogenic and showed a variable penetrance when present separately; when occurring together, the onset was very early, within the third decade of life. Genetic screening of the PRNP gene becomes of major importance in early onset autosomal dominant dementia.

Pages 421-454
Yoelvis García, Juan Carlos López-Ramos, Lydia Giménez-Llort, Susana Revilla, Rafael Guerra, Agnès Gruart, Frank M. LaFerla, Rosa Cristòfol, José M Delgado-García, Coral Sanfeliu (Handling Associate Editor: Gemma Casadesus)
Physical exercise protects against Alzheimer’s disease in 3xTg-AD mice
Abstract: Physical exercise is considered to exert a positive neurophysiological effect that helps to maintain normal brain activity in the elderly. Expectations that it could help to fight Alzheimer’s disease (AD) were recently raised. This study analyzed the effects of different patterns of physical exercise on the 3xTg-AD mouse. Male and female 3xTg-AD mice at an early pathological stage (4-month-old) have had free access to a running wheel for 1 month, whereas mice at a moderate pathological stage (7-month-old) have had access either during 1 or 6 months. The non-transgenic mouse strain was used as a control. Parallel animal groups were housed in conventional conditions. Cognitive loss and behavioral and psychological symptoms of dementia (BPSD)-like behaviors were present in the 3xTg-AD mice along with alteration in synaptic function and ong-term potentiation impairment in vivo. Brain tissue showed AD-pathology and oxidative-related changes. Disturbances were more severe at the older age tested. Oxidative stress was higher in males but other changes were similar or higher in females. Exercise treatment ameliorated cognitive deterioration and BPSD-like behaviors such as anxiety and the startle response. Synaptic changes were partially protected by exercise. Oxidative stress was reduced. The best neuroprotection was generally obtained after 6 months of exercise in 7-month-old 3xTg-AD mice. Improved sensorimotor function and brain tissue antioxidant defence were induced in both 3xTg-AD and NonTg mice. Therefore, the benefits of aerobic physical exercise on synapse, redox homeostasis, and general brain function demonstrated in the 3xTg-AD mouse further support the value of this healthy life-style against neurodegeneration.

Pages 455-474
Massimo Filippi, Federica Agosta (Handling Associate Editor: Daniela Galimberti)
Structural and functional network connectivity breakdown in Alzheimer’s disease studied with magnetic resonance imaging techniques.
Abstract: Patients with Alzheimer's disease (AD) experience a brain network breakdown, reflecting disconnection at both the structural and functional system level. Resting-state (RS) functional MRI (fMRI) studies demonstrated that the regional coherence of the fMRI signal is significantly altered in patients with AD and amnestic mild cognitive impairment. Diffusion tensor (DT) MRI has made it possible to track fiber bundle projections across the brain, revealing a substantially abnormal interplay of “critical” white matter tracts in these conditions. The observed agreement between the results of RS fMRI and DT MRI tractography studies in healthy individuals is encouraging and offers interesting hypotheses to be tested in patients with AD, aMCI, and other dementias in order to improve our understanding of their pathobiology in vivo. In this review, we describe the major findings obtained in AD using RS fMRI and DT MRI tractography, and discuss how the relationship between structure and function of the brain networks in AD may be better understood through the application of MR-based technology. This research endeavor holds a great promise in clarifying the mechanisms of cognitive decline in complex chronic neurodegenerative disorders.

Pages 475-484
Anna M. Bennet, Chandra A. Reynolds, Ulrika K. Eriksson, Mun-gwan Hong, Kaj Blennow, Margaret Gatz, Andrey Alexeyenko, Nancy L. Pedersen, Jonathan A. Prince (Handling Associate Editor: Emilio Di Maria)
Genetic Association of sequence variants near AGER/NOTCH4 and Dementia
Abstract: We performed a survey of sequence variation in a series of 20 genes involved in inflammation-related pathways for association with dementia risk in twin and unrelated case-control samples consisting in total of 1462 Swedish dementia cases and 1929 controls. For a total of 218 tested genetic markers, strong evidence was obtained implicating a region near AGER and NOTCH4 on chromosome 6p with replication across both samples and maximum combined significance at marker rs1800625 (OR = 1.37, 95% CI 1.19-1.56, p = 1.36 x 10-6). Imputation of the associated genomic interval provided an improved signal at rs8365, near the 3’UTR of AGER (p = 7.34 x 10-7). The associated region extends 120kb encompassing 11 candidate genes. While AGER encodes a key receptor for amyloid-β protein, an analysis of network context based upon genes now confirmed to contribute to dementia risk (AβPP, PSEN1, PSEN2, CR1, CLU, PICALM, and APOE) suggested strong functional coupling to NOTCH4,with no significant coupling to the remaining candidates. The implicated region occurs in the broad HLA locus on chromosome 6p, but associated markers were not in strong LD with known variants that regulate HLA gene function, suggesting that this may represent a signal distinct from immune-system pathways.

Supplementary Data for Bennet et al. article (PDF)

Pages 485-493
Chih-Cheng Hsu, Mark L Wahlqvist, Meei-Shyuan Lee, Hsin-Ni Tsai (Handling Associate Editor: Angelika Bierhaus)
Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin
Abstract: To determine incidence of dementia in type 2 diabetic (T2DM) patients, and whether there are adverse or favorable effects of oral agents (OA) in DM, we obtained a representative cohort of 800,000 from Taiwan’s National Health Insurance database. Those who, as of on January 1, 2000, were 50 years or older and dementia free (n=127,209) were followed until December 31, 2007, in relation to absence (n=101,816) or presence (n=25,393) of T2DM, and whether any OA was used. Dementia was ascertained by ICD9-CM or A-code. Dementia incidence densities (DID) and fully adjusted Cox proportional hazard models were used to estimate association between dementia, DM, and OA. Notably, DID (per 10,000 person-years) was markedly increased with DM (without medication), compared to DM free subjects (119 versus 46). Using non-DM as reference, the adjusted hazard ratios (HRs) (95% confidence interval) for DM without and with OA were 2.41 (2.17–2.66) and 1.62 (1.49–1.77), respectively. For T2DM, compared with no medication, sulfonylureas alone reduced the HR from 1 to 0.85 (0.71–1.01), metformin alone to 0.76 (0.58–0.98), while with combined oral therapy the HR was 0.65 (0.56–0.74). Adjustments included cerebrovascular diseases so that non-stroke related dementias were found to be decreased in DM with sulfonylurea and metformin therapy. T2DM increases the risk of dementia more than 2-fold. On the other hand, sulfonylureas may decrease the risk of dementia, as does metformin; together, these 2 OAs decrease the risk of dementia in T2DM patients by 35% over 8 years.

Pages 495-506
Michael Schöll, Ove Almkvist, Nenad Bogdanovic, Anders Wall, Bengt Långström, Matti Viitanen, Agneta Nordberg
Time course of glucose metabolism in relation to cognitive performance and postmortem neuropathology in Met146Val PSEN1 mutation carriers
Abstract: Studies in carriers of mutations that cause early-onset familial Alzheimer’s disease (eoFAD) are of significant interest. We showed previously that regional glucose hypometabolism could be detected many years before disease onset in presenilin 1 (PSEN1) mutation carriers. Here we studied four members of a family with a Met146Val PSEN1 mutation, two symptomatic carriers and two non-carriers, longitudinally with 18F-FDG PET over a period of about two and four years, respectively. The two mutation carriers showed global cortical glucose hypometabolism over time with the most distinct decline occurring in the posterior cingulate, the parietal and parietotemporal cortex, which was also observed when compared with a group of 23 healthy controls and a group 27 sporadic Alzheimer’s disease (sAD) patients. This decline correlated with cognitive deterioration over time as measured by neuropsychological tests. Postmortem examination of brain tissue revealed substantially elevated levels of AD type neuropathology in terms of neuritic plaques and neurofibrillary tangles in the two mutation carriers compared with a reference group of sAD patients. In the mutation carriers, the amount of neuritic plaques but not neurofibrillary tangles correlated hereby significantly with regional glucose metabolism as measured by 18F-FDG on the last scanning occasions, which were performed four and approximately five years before death, respectively. We here show that FDG PET can depict in vivo the aggressive disease progression in eoFAD mutation carriers in relationship to neuropathology.

Pages 507-517
Miki Igarashi, Kaizong Ma, Fei Gao, Hyung-Wook Kim, Stanley I. Rapoport, Jagadeesh S. Rao
Disturbed Choline Plasmalogen and Phospholipid Fatty Acid Concentrations in Alzheimer’s Disease Prefrontal Cortex
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by brain deposition of senile (neuritic) plaques containing amyloid-β, neurofibrillary tangles, synaptic loss, neuroinflammation, and overexpression of arachidonic acid (AA, 20:4n-6) metabolizing enzymes. Lipid concentration changes have been reported in different brain regions, but often partially or as a percent of the total concentration. In this study, we measured absolute concentrations (per gram wet weight) of a wide range of lipids in postmortem prefrontal cortex (Brodmann area 9) from 10 AD patients and 9 non-AD controls. Mean total brain lipid, phospholipid, cholesterol, and triglyceride concentrations did not differ significantly between AD and controls. There was a significant 73% decrease in plasmalogen choline, but no difference in other measured phospholipids. Fatty acid concentrations in total phospholipid did not differ from control. However, docosahexaenoic acid (DHA, 22:6n-3) was reduced in ethanolamine glycerophospholipid and choline glycerophospholipid, but increased in phosphatidylinositol. AA was reduced in choline glycerophospholipid, but increased in phosphatidylinositol, while docosatetraenoic acid (22:4n-6), an AA elongation product, was reduced in total brain lipid, cholesteryl ester and triglyceride. These lipid changes, which suggest extensive membrane remodeling, may contribute to membrane instability and synaptic loss in AD and reflect neuroinflammation.

Pages 519-524
Yun Jeong Hong, Bora Yoon, Yong S. Shim, A-Hyun Cho, Hae-Eun Shin, Yeong-In Kim, Sang Yun Kim, Dong Won Yang (Handling Associate Editor: George Bartzokis)
APOE ε4 Allele Status in Korean Dementia Patients with Severe White Matter Hyperintensities
Abstract: Few studies have investigated the apolipoprotein E (APOE) ε4 allele status of dementia patients with severe white matter hyperintensities (WMH). In this study, we aimed to characterize the APOE epsilon genotypes and clinical features of dementia patients with severe WMH. 439 patients with dementia and 152 subjects with normal cognition (NC) were recruited from multiple centers in Korea, known as the Clinical Research Center for Dementia of South Korea (CREDOS), since November 2005. The WMH were rated using the scale that had been developed by the CREDOS study. Dementia patients with minimal WMH were considered to have Alzheimer’s disease (AD) without WMH (AD-WMH: 325), and those with severe WMH were considered to have Subcortical Ischemic Vascular Dementia (SIVD: 50) or AD with severe WMH (AD+WMH: 64). Comparisons of APOE ε4 allelic prevalence were performed using chi-square analysis. The APOE ε4 allele was more prevalent in those with AD than in those with SIVD and NC (p < 0.001). It was not more prevalent in those with SIVD than in those with NC (p = 0.169). APOE ε4 allele status in AD+WMH did not differ from that in AD-WMH (p = 0.625). The APOE ε4 allele was more prevalent in those with AD than in those with SIVD. APOE ε4 may not be associated with SIVD although it is one of the vascular risk factors.

Pages 525-535
Yu Guang*, Yi Li*, Qing Tian, Rong Liu, Qun Wang, Jian-Zhi Wang, Xiaochuan Wang *These authors contributed equally to the paper.
Berberine attenuates calyculin A-induced cytotoxicity and tau hyperphosphorylation in HEK293 cells
Abstract: The Chinese herb berberine has versatile health effects. Recent reports indicate that berberine has the potential to prevent and treat Alzheimer's disease (AD). In the present study, we employed tau-expressing HEK293 cells (HEK293/tau) treated with calyculin-A as a cellular model to investigate the roles of berberine in cell viability, tau phosphorylation, and oxidative stress. We found a significant reduction of calyculin A-induced tau hyperphosphorylation at Ser198/199/202, Ser396, Ser404, Thr205, and Thr231 24 h after treatment with 20 μg/ml berberine. Berberine also restored protein phosphates 2A activity and reversed glycogen synthase kinase-3β (GSK-3β) activation, as determined by phosphatase activity assay and GSK-3β phosphorylation at Tyr216 and Ser9, respectively. Furthermore, berberine reversed both the increase of malondialdehyde and the decrease of superoxide dismutase activity induced by calyculin A, indicating its role in anti-oxidative stress. Our findings suggest that berberine may be a potential therapeutic drug for AD.

Pages 537-546
Per Johansson*, Niklas Mattsson*, Oskar Hansson, Anders Wallin, Jan-Ove Johansson, Ulf Andreasson, Henrik Zetterberg, Kaj Blennow, Johan Svensson *These authors contributed equally to this work
Cerebrospinal Fluid Biomarkers for Alzheimer’s disease: Diagnostic Performance in a Homogeneous Mono-Center Population
Abstract: The cerebrospinal fluid (CSF) biomarkers amyloid-β (Aβ)1-42, T-tau, and P-tau have good diagnostic accuracy for clinically diagnosed Alzheimer’s disease (AD). However, in multi-center studies, the predictive values of the CSF biomarkers have been lower, possibly due to differences in procedures for lumbar puncture and CSF handling and storage, and to differences in patient populations, clinical evaluations, and diagnostic procedures. Here we investigate the diagnostic accuracy of CSF biomarkers in a well defined homogeneous mono-center population. We also evaluate an extended panel of amyloid related biomarkers. Sixty consecutive patients admitted for cognitive impairment to a memory clinic were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n=32), patients with stable MCI (n=13), patients with other dementias diagnosed at primary evaluation or upon follow-up (n=15), and healthy controls (n=20). CSF was analyzed for Aβ1-42, T-tau, P-tau, Aβx-38, Aβx-40, Aβx-42, sAβPPα, and sAβPPβ. In multivariate analysis, the core biomarkers Aβ1-42, T-tau, and P-tau demonstrated a high ability to diagnose AD versus the combined groups of controls and stable MCI, with an area under the receiver operating characteristic curve (AUROC) of 0.97 (95% CI 0.93-1.00, p<0.0001). The additional biomarkers only marginally increased AUROC to 0.98 (95% CI 0.95-1.00, p<0.0001), this increase mainly mediated by Aβx-42. In conclusion, CSF biomarkers Aβ1-42, T-tau, and P-tau have very high diagnostic accuracy in a well defined cohort of untreated patients, demonstrating the excellent potency of CSF biomarkers to identify pathological processes in AD when a stringent analytical protocol is used.

Pages 547-557
Stephen W. Scheff, Douglas A. Price, Frederick A. Schmitt, Melissa A. Scheff, Elliott J. Mufson
Synaptic Loss in the Inferior Temporal Gyrus in Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a slowly progressing form of dementia characterized in its earliest stages as a loss of memory. Individuals with amnestic mild cognitive impairment (aMCI) may be in the earliest stages of the disease and represent an opportunity to identify pathological changes related to the progression of AD. Synaptic loss is one of the hallmarks of AD and associated with cognitive impairment. The inferior temporal gyrus plays an important role in verbal fluency, a cognitive function affected early in the onset of AD. Unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the inferior temporal gyrus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI had significantly fewer synapses (36%) compared to individuals with no cognitive impairment. Individuals with AD showed a loss of synapses very similar to the aMCI cohort.  Synaptic numbers correlated highly with Mini Mental State Examination scores and a test of category verbal fluency. These results demonstrate that the inferior temporal gyrus is affected during the prodromal stage of the disease and may underlie some of the early AD-related clinical dysfunctions.

Pages 559-568
Alessandra Marengoni, Laura Fratiglioni, Stefania Bandinelli, Luigi Ferrucci
Socioeconomic Status During Lifetime and Cognitive Impairment No-Dementia in Late Life: The Population-Based Aging in the Chianti Area (InCHIANTI) Study
Abstract: 1012 dementia-free elderly (60-98 years old) enrolled in the InChianti Study (Italy) were evaluated at baseline (1998-2000) and at 3-year follow-up (2001-2003) with the aim of analyzing the association of lifetime socioeconomic status (SES) with prevalent and incident cognitive impairment no-dementia (CIND). SES was defined from information on formal education, longest held occupation, and financial conditions through life. CIND was defined as age-adjusted Mini-Mental State Examination score one standard deviation below the baseline mean score of participants without dementia. Logistic regression and Cox proportional-hazards models were used to estimate the association of SES with CIND. Demographics, occupation characteristics (i.e., job stress and physical demand), cardiovascular diseases, diabetes, apolipoprotein E (APOE) genotype, smoking, alcohol consumption, depressive symptoms, and C-reactive protein were considered potential confounders. Prevalence of CIND was 17.7%. In the fully adjusted model, low education (OR=2.1;95% confidence intervals, CI=1.4 to 3.2) was associated with prevalent CIND. Incidence rate of CIND was 66.0 per 1000 person-years. Low education (HR=1.7; 95%CI= 1.04 to 2.6) and manual occupation (HR=1.9;95%CI=1.0 to 3.6) were associated with incident CIND. Among covariates, high job-related physical demand was associated with both prevalent and incident CIND (OR=1.6;95%CI=1.1 to 2.4 and HR=1.5; 95%CI=1.0 to 2.3). After stratification for education, manual occupation was still associated with CIND among participants with high education (HR=2.2;95%CI=1.2 to 4.3 versus HR=1.4;95%CI=0.2 to 10.4 among those with low education). Proxy markers of lifetime SES (low education, manual occupation and high physical demand) are cross-sectional correlates of CIND and predict incident CIND over a three-year follow-up.

Pages 569-586
Vuokko Antonini, Agostino Marrazzo, Giulio Kleiner, Marino Coradazzi, Simone Ronsisvalle, Orazio Prezzavento, Giuseppe Ronsisvalle, Giampiero Leanza (Handling Associate Editor: Ottavio Arancio)
Anti-Amnesic and Neuroprotective Actions of the Sigma-1 Receptor Agonist (-)-MR22 in Rats with Selective Cholinergic Lesion and Amyloid Infusion
Abstract: Sigma-1 receptor agonists have recently attracted much attention as potential therapeutic drugs for cognitive and affective disorders, however, it is still unclear whether they act via modulation of transmitter release or activation of sigma-1 receptors in memory-related brain regions. In the present study, we have investigated the anti-amnesic and neuroprotective actions of the compound (-)-methyl (1S,2R)-2-{[1-adamantyl(methyl)amino]methyl}-1-phenylcyclopropane-carboxylate) [(-)-MR22], a selective sigma-1 receptor agonist able to protect cultured cortical neurons from amyloid toxicity. To this aim, cognitive deficits, cholinergic loss, and amyloid peptide accumulation were obtained in the rat by simultaneous injections of a selective immunotoxin and pre-aggregated amyloid peptide into the basal forebrain and the hippocampus, respectively. At about five-six weeks post-lesion, the double-lesioned animals exhibited dramatic deficits in spatial learning and memory, whereas animals with single injections of either compound were not or only marginally affected, in spite of equally severe cholinergic loss or amyloid deposition. Administration of (-)-MR22 appeared to reverse cognitive impairments in double lesioned animals, whereas pre-treatment with the selective sigma-1 antagonist BD1047 abolished this effect. Moreover, (-)-MR22 normalized the levels of cell-associated amyloid-β protein precursor (AβPP) in the neocortex and hippocampus, thus sustaining a non-amyloidogenic AβPP processing. By contrast, treatment with (-)-MR22 produced no effects whatsoever in intact animals. Thus, sigma-1 receptor agonists such as (-)-MR22 may ameliorate perturbed cognitive abilities and exert a protective action onto target neurons, holding promises as viable tools for memory enhancement and neuroprotection.

Pages 587-597
Olivia Belbin*, Kristelle Brown*, Hui Shi, Christopher Medway, Richard Abraham, Peter Passmore, David Mann, A. David Smith, Clive Holmes, Bernadette McGuinness, David Craig, Donald Warden, Reinhard Heun, Heike Kölsch, Seth Love, Noor Kalsheker, Julie Williams, Michael J Owen, Minerva Carrasquillo, Steven Younkin, Kevin Morgan#, Patrick G Kehoe# (Handling Associate Editor: Francesco Panza) *These authors contributed equally to this work. #These authors were both principal investigators for this study
A multi-center study of ACE and the risk of late-onset Alzheimer’s disease
Abstract: A key pathological feature of late-onset Alzheimer’s disease (LOAD) is the abnormal extracellular accumulation of the amyloid-β (Aβ) peptide. Thus, altered Aβ degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aβ-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association with LOAD in ten Caucasian case-control populations (n=8,212). No association was found using multiple logistic models (all p>0.09). We found no population heterogeneity (all p>0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR=1.00), rs4291 (OR=0.97), or rs1800764 (OR=0.99). Although we found no haplotypic association in our complete dataset (p=0.51), a significant global haplotypic p-value was observed in one population (p=0.007) due to an association of the H3 haplotype (OR=0.72, p=0.02) and a trend towards an association of H4 (OR=1.38, p=0.09) and H7 (OR=2.07, p=0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies.

Pages 599-607
Lisa M. Bloudek, D. Eldon Spackman, David L. Veenstra, Sean D. Sullivan
CDR State Transition Probabilities in Alzheimer’s Disease with and without Cholinesterase Inhibitor Intervention in an Observational Cohort
Abstract: Cholinesterase inhibitors and memantine are medications used in the treatment of Alzheimer’s disease (AD). These agents have been shown to reduce the rate AD progression in randomized trials. The objective of this study is to evaluate the association between treatment with cholinesterase inhibitors or memantine and the probability of transitioning to a more severe Clinical Dementia Rating (CDR) state. Analysis was limited to possible or probable AD patients from NACC-UDS with three or more observations, baseline CDR score of 0.5 or 1, and without reported use AD drugs at enrollment. Use of an AD drug at any observation after baseline was classified as treatment. Odds of CDR stage were calculated by multinomial logistic regression controlling for baseline age, baseline MMSE score, education, marital status, race, gender, place of residence, and time since last measure. The resulting coefficients from logistic regression were used to calculate transitional probabilities. A total of 1,114 patients were included. No differences were observed in the probability of transitioning to more severe CDR states based on treatment, but treated patients had lower odds of death, OR 0.49 (95% CI 0.31 to 0.79) compared to untreated. Ultimately, this study failed to detect a difference in the probability of progressing to a more severe AD state as a result of treatment in an observational cohort of AD patients, but is limited by non-randomized treatment selection and small dataset. The NACC-UDS dataset is ongoing and this analysis may be improved if repeated when more data is available.

Page 609
Book Review: Following Charcot: A Forgotten History of Neurology and Psychiatry by J. Bougousslavsky, S. Karger AG, Basel, 2011, 208 p. Reviewed by Alan Lerner.

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