Volume 34, Number 1, February 2013

Pages 1-114
Review
Wolfgang Froestl, Andrea Pfeifer, Andreas Muhs
Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs
Abstract: Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer’s disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs, meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years.

Pages 115-131
Review
Gladys L. Caldeira, I. Luisa Ferreira, A. Cristina Rego
Impaired Transcription in Alzheimer’s Disease: Key Role in Mitochondrial Dysfunction and Oxidative Stress
Abstract: Alzheimer’s disease (AD) is the major cause of dementia in the world. Abnormal extracellular accumulation of amyloid-β (Aβ) peptide and tau hyperphosphorylation, forming neurofibrillary tangles in the brain, are hallmarks of the disease. Oxidative stress, neuroinflammation, and mitochondrial and synaptic dysfunction are also observed in AD and often correlated to intracellular Aβ. This peptide results from the cleavage of the amyloid-β protein precursor by β- and γ-secretases and tends to be secreted after its production. However, secreted Aβ can be internalized by the interaction with membrane receptors, namely N-methyl-D-aspartate receptors, advanced glycation end products receptors, and/or alpha 7 nicotinic acetylcholine receptors. Inside the cell, Aβ interacts with several organelles, including mitochondria and nucleus, and there is growing evidence pointing to a possible role of Aβ in the regulation of gene transcription. Accordingly, transcriptional deregulation was observed in several AD models and human samples from AD patients through modified expression, phosphorylation levels, function, and subcellular localization of some transcription factors, resulting in the suppression of neuroprotective transcription both in the nucleus and the mitochondria. In this review we focus on key transcription regulators related with mitochondrial biogenesis and antioxidant defenses that seem to be altered in AD models and also on the role of intranuclear Aβ in the pathogenesis of the disease.

Pages 133-137
Short Communication
María Montañés, Diego Casabona, Leticia Sarasa, Pedro Pesini, Manuel Sarasa
Prevention of Amyloid-β Fibril Formation Using Antibodies against the C-terminal Region of Amyloid-β1-40 and Amyloid-β1-42
Abstract: Alzheimer’s disease is characterized by the abnormal aggregation of amyloid-β (Aβ)1-40 and Aβ1-42 peptides into fibrils. In this work, we analyzed the kinetics of Aβ1-40 and Aβ1-42 fibril formation in vitro using Thioflavin T fluorescence. We synthesized high-purity peptides and performed a hexafluoro-2-propanol pre-treatment to yield uniform peptide solutions as starting materials. We found that the aggregation is clearly affected by the presence of sub-millimolar quantities of antibodies against the C-terminal region of the peptides. Because the fibrillization of these peptides is closely related to the pathogenesis of Alzheimer’s disease, blocking this process may provide significant therapeutic benefit.

Pages 139-144
Short Communication
David L. Perez*, Bradford C. Dickerson, Scott M. McGinnis, Daisy Sapolsky, Keith Johnson, Meghan Searl, Kirk R. Daffner* (Handling Associate Editor: Mira Didic) *These authors contributed equally to this manuscript.
You Don’t Say: Dynamic Aphasia, Another Variant of Primary Progressive Aphasia?
Abstract: Primary progressive aphasia (PPA) is a language predominant neurodegenerative disorder that has three recognized variants: nonfluent/agrammatic, semantic, and logopenic. This report describes a 60-year-old man who presented with a progressive decline in verbal output that does not fit the currently accepted PPA subtypes. The patient exhibited a paucity of verbal output and impaired phonemic fluency with minimal associated language, cognitive, or behavioral deficits. Focal cortical thinning/hypometabolism of the left superior frontal region and a cerebrospinal fluid profile not consistent with Alzheimer’s disease pathology were identified. This case of isolated progressive dynamic aphasia extends the current boundaries of PPA diagnostic variants.

Pages 145-154
Rebecca Dwyer*, Olivia Anna Skrobot*, James Dwyer, Marcus Munafo, Patrick Gavin Kehoe *These authors contributed equally to this work.
Using Alzgene-Like Approaches to Investigate Susceptibility Genes for Vascular Cognitive Impairment
Abstract: Vascular cognitive impairment (VCI), including vascular dementia, is the second most common dementia after Alzheimer’s disease. Despite its prevalence, the genetic etiology of sporadic VCI is largely unknown. We conducted a systematic review of all published genetic association studies of forms of sporadic VCI prior to 6 July 2012. An initial pool of 229 gene association studies yielded 104 papers (72 polymorphisms from 47 genes) that met inclusion criteria for analysis. Systematic meta-analysis was conducted on 6 polymorphisms (which had 3 or more published case-control cohorts from 69 papers) in the APOE, ACT, ACE, MTHFR, PON1, and PSEN-1 genes. Associations of increased risk for VCI were found for APOE ε4 (1.818 (95% CI=1.611-2.053), p=<0.001; n=3,554 cases, n=12,277 controls) and MTHFR rs1801133 (1.323 (95% CI=1.061-1.650) p=0.013); n=659 cases, n=981 controls). There was marginal evidence of a protective effect for APOE ε2 (0.885 (95% CI= 0.783-0.999), p=0.048; n=3,320 cases, n=10,786 controls). This systematic study of all published genetic association studies of sporadic VCI supports MTHFR and APOE as susceptibility genes for VCI. It also shows the utility of meta-analysis as a tool to identify potential candidate genes from numerous individual small-scale studies of diseases where sample recruitment may be limited for a variety of practical reasons.

Supplementary Data for Dwyer et al. article (PDF)

Pages 155-170
Mathew T. Mizwicki, Guanghao Liu, Milan Fiala, Larry Magpantay, James Sayre, Avi Siani, Michelle Mahanian, Rachel Weitzman, Eric Hayden, Mark J. Rosenthal, Ilka Nemere, John Ringman, David B. Teplow
1α,25-Dihydroxyvitamin D3 and Resolvin D1 Retune the Balance between Amyloid-β Phagocytosis and Inflammation in Alzheimer’s Disease Patients
Abstract: As immune defects in amyloid-β (Aβ) phagocytosis and degradation underlie Aβ deposition and inflammation in Alzheimer’s disease (AD) brain, better understanding of the relation between Aβ phagocytosis and inflammation could lead to promising preventive strategies. We tested two immune modulators in peripheral blood mononuclear cells (PBMCs) of AD patients and controls: 1α,25(OH)2-vitamin D3 (1,25D3) and resolvin D1 (RvD1). Both 1,25D3 and RvD1 improved phagocytosis of FAM-Aβ by AD macrophages and inhibited fibrillar Aβ-induced apoptosis. The action of 1,25D3 depended on the nuclear vitamin D and the protein disulfide isomerase A3 receptors, whereas RvD1 required the chemokine receptor, GPR32. The activities of 1,25D3 and RvD1 commonly required intracellular calcium, MEK1/2, PKA, and PI3K signaling; however, the effect of RvD1 was more sensitive to pertussis toxin. In this case study, the AD patients: a) showed significant transcriptional up regulation of IL1RN, ITGB2, and NFκB; and b) revealed two distinct groups when compared to controls: group 1 decreased and group 2 increased transcription of TLRs, IL-1, IL1R1 and chemokines. In the PBMCs/macrophages of both groups, soluble Aβ (sAβ) increased the transcription/secretion of cytokines (e.g., IL1 and IL6) and chemokines (e.g., CCLs and CXCLs) and 1,25D3/RvD1 reversed most of the sAβ effects. However, they both further increased the expression of IL1 in the group 1, sβ-treated cells. We conclude that in vitro, 1,25D3 and RvD1 rebalance inflammation to promote Aβ phagocytosis, and suggest that low vitamin D3 and docosahexaenoic acid intake and/or poor anabolic production of 1,25D3/RvD1 in PBMCs could contribute to AD onset/pathology.

Supplementary Data for Mizwicki et al. article (PDF)

Pages 171-182
Alan Rembach, James D. Doecke, Blaine R. Roberts, Andrew D. Watt, Noel G. Faux, Irene Volitakis, Kelly K. Pertile, Rebecca L. Rumble, Brett O. Trounson, Christopher J. Fowler, William Wilson, Kathryn A. Ellis, Ralph N. Martins, Christopher C. Rowe, Victor L. Villemagne, David Ames, Colin L Masters, AIBL research group, Ashley I. Bush
Longitudinal Analysis of Serum Copper and Ceruloplasmin in Alzheimer’s Disease
Abstract: Background: Several studies have reported that peripheral levels of copper and ceruloplasmin (CP) can differentiate patients with Alzheimer’s disease (AD) from non-AD cases. The aim of this study was to determine the diagnostic value of serum copper, CP, and non-CP copper levels in a large cohort of AD subjects. Methods: Serum copper and CP concentrations were measured at baseline and at 18-months in participants from the Australian Imaging Biomarkers and Lifestyle Study of Ageing. Cross-sectional and longitudinal analyses were conducted using both univariate and multivariate testing adjusting for age, gender, total protein, and ApoE ε4 genotype status. Results: There was no significant difference in levels of serum copper or CP between the AD and healthy control groups, however, we identified a near-significant decrease in non-CP copper in the mild cognitive impairment and AD groups at baseline (p=0.02) that was significant at 18-months (p=0.003). Conclusion: Our results suggest that there may be decreased non-CP copper levels in mild cognitive impairment and AD, which is consistent with diminished copper-dependent biochemical activities described in AD.

Supplementary Data for Rembach et al. article (PDF)

Pages 183-190
Rafael Dal-Ré, Karine Fauria, Nina Gramunt, José Luis Molinuevo (Handling Associate Editor: Josep Garre-Olmo)
Clinical Observational Research on Alzheimer’s Disease: What Clinical Trial Registries Can Tell
Abstract: This study describes the main characteristics of ongoing observational studies on Alzheimer’s disease (AD) to help identify any important research gaps. A search through the WHO International Clinical Trials Registry Platform and on the Primary Registries was conducted on 9 June 2012. The descriptors ‘recruiting’ or ‘open’ were used to describe a study’s recruitment status. 62 studies are being conducted in 18 countries (Australia, Far-East, Middle-East, North America, and Western Europe). The US and France are involved in 55% of these studies. The studies aimed to recruit 20 to 10,000 participants, lasting 8 months to 24 years; 46% are case-control, whereas 44% are cohort studies; 60% and 34% are longitudinal and cross-sectional, respectively. The majority are sponsored by hospitals, universities, medical centers, or public health systems (63%), and are conducted in single centers (55%). 37 use imaging (MRI, PET, SPECT), 18 conduct lumbar puncture, 21 collect DNA and/or RNA, and 15 collect ApoE genotyping. 17 studies are medium-term prospective disease progression studies, the majority to assess mild cognitive impairment (MCI) or/and AD progression; only 3 are on cognitively normal older people at risk (2 studies, n=180) or not (1 study, n<200) of developing MCI. Observational studies are being conducted in few countries, with very few in low and middle-income countries where the majority of AD patients live. There is a remarkable interest in disease progression studies; however, longitudinal, long-term studies, on cognitively normal middle-age individuals, of key importance to try to fully understand the preclinical phase of AD, are lacking.

Supplementary Data for Dal-Ré et al. article (PDF)

Pages 191-202
Tania Zieschang, Michael Schwenk, Peter Oster, Klaus Hauer (Handling Associate Editor: Jeff Burns)
Sustainability of Motor Training Effects in Older People with Dementia
Abstract: Evidence for sustainability of motor training effects in people with dementia is lacking. To examine whether the substantial improvements in motor performance achieved through a three-month specialized, standardized motor training were sustained, the participants of the randomized controlled trial were re-evaluated nine months after training had ceased. As part of a comprehensive study, participants with confirmed mild to moderate dementia underwent a progressive resistance and functional group training specifically developed for patients with dementia (intervention, n=40) compared to a low-intensity motor placebo activity (control, n=51). Primary and secondary outcome measures for maximal strength and function were measured before the start of the training (T1), directly after training ceased (T2), three months after training ceased (T3) and—the focus of this paper—nine months after training ceased (T4). Even after nine months without training, the gains in functional performance were sustained with significant group differences in the primary endpoint (five-chair-rise, relative change: IG:-8.54 (22.57) versus CG:+10.70 (45.89) s, p=0.014, effect size ηp2 =0.067). Other functional tests, such as walking speed and POMA (Tinetti), confirmed this result in the secondary analysis. Strength, as measured by the primary endpoint 1-Repetition Maximum (1RM) was still elevated (time effect for T1 versus T4: 148.68 ± 57.86 versus 172.79 ± 68.19 kg, p<0.001, effect size ηp2 =0.157), but between-group differences disappeared (relative change: maximal strength, IG: 22.75 (40.66) versus CG: 15.60 (39.26), p=0.369). The study found that intensive dementia-specific motor training sustainably improved functional performance of patients with dementia nine months after cessation of training.

Pages 203-213
Maoping Tang*, Zhaoxia Wang*, Ying Zhou, Wangjie Xu, Shengtian Li, Lianyun Wang, Dongqing Wei, Zhongdong Qiao *These authors contributed equally to this paper.
A Novel Drug Candidate for Alzheimer’s Disease Treatment: gx-50 Derived from Zanthoxylum Bungeanum
Abstract: This study focused on a promising drug candidate , N-[2-(3,4-dimethoxyphenyl)ethyl]- 3-phenyl-acrylamide (gx-50), a compound extracted from Sichuan pepper (Zanthoxylum bungeanum), to determine whether it would be an effective therapeutic for Alzheimer’s disease (AD) via biological experiments. In vivo, we determined the pharmacokinetic profile of gx-50 and evaluated the effect of gx-50 on the cognitive abilities of amyloid-β protein precursor transgenic (AβPP-Tg) mice by Morris water maze testing. In addition, we examined the effects of gx-50 on amyloid-β (Aβ) oligomers in the brains of AβPP-Tg mice by immunohistochemistry. In vitro, we observed a direct effect of gx-50 on Aβ oligomers by atomic force microscopy, detected the neuroprotective effects of gx-50 by western blotting and cell apoptosis assays, and measured its effects on intracellular calcium currents by laser confocal microscopy. Experiments in vivo showed that gx-50 could penetrate the blood brain barrier and improve the cognitive abilities of mice. Moreover, gx-50 treatment decreased the accumulation of Aβ oligomers in the cerebral cortex. The results in vitro demonstrated that gx-50 could disassemble Aβ oligomers, inhibit Aβ-induced neuronal apoptosis and apoptotic gene expression, and reduce neuronal calcium toxicity. These results strongly suggest that gx-50 is a potential candidate drug for treating AD.

Supplementary Data for Tang et al. article (PDF)
Supplementary Video 1 for Tang et al. (avi)
Supplementary Video 2 for Tang et al. (avi)
Supplementary Video 3 for Tang et al. (avi)

Pages 215-230
Eleni Pontiki, Christos Kontogiorgis, Yanan Xu, Dimitra Hadjipavlou-Litina, Yuan Luo (Handling Associate Editor: Thomas Shea)
New Lipoxygenase Inhibitors of Reactive Oxygen Species Production in Cellular Models of Amyloid (A2) Toxicities
Abstract: Neuroinflammation and oxidative stress are contributing factors to neurodegeneration in physiological aging as well as in age-related neurological disorders. Neuroinflammation can be both a cause and a result of chronic oxidative stress. The role of the oxidative stress and free radicals in the development of Alzheimer’s disease (AD) is currently the focus of many studies. Hydrogen peroxide (H2O2) in AD is thought to be associated with amyloid-β (Aβ) damage in cells. Aryl acetic acid derivatives were previously reported to be potent anti-inflammatory and antioxidant agents. In the present study, aryl acetic acid derivatives were tested as H2O2 scavengers using the DCF assay on two types of neuronal cells: a) the wild type N2a neuroblastoma cells; and b) the AβPP/PS1 transgenic cell line expressing Aβ. The scavenging activity of these agents and their protective role against cell death was demonstrated in both cell types. Our results suggest that these compounds could be used as a template in the design of novel therapeutic agents for AD.

Pages 231-238
Matteo Tagliapietra, Gianluigi Zanusso, Michele Fiorini, Nicola Bonetto, Giulia Zarantonello, Alberto Zambon, Mario Ermani, Salvatore Monaco, Renzo Manara, Annachiara Cagnin
Accuracy of Diagnostic Criteria for Sporadic Creutzfeldt-Jakob Disease among Rapidly Progressive Dementia
Abstract: Rapidly progressive dementia (RPD) is a rare presentation of different neurological disorders characterized by cognitive impairment leading to loss of functional independence within 24 months or less. The increasing recognition of treatable non-prion causes of RPD has made the differential diagnosis with sporadic Creutzfeldt-Jakob disease (sCJD) of crucial importance. We therefore assessed the frequency of different etiologies of RPD and evaluated the accuracy of newly proposed diagnostic criteria for sCJD. Clinical records of patients with RPD referred to Memory Clinic between 2007 and 2012 were retrospectively analyzed. The accuracy of diagnostic criteria for sCJD was evaluated by: a) MRI images in DWI and FLAIR sequences; and (b) CSF 14-3-3 protein. In addition, CSF total tau protein level was also assessed. Final diagnosis was obtained after a 1-year follow-up or after autopsy. Among 37 patients with RPD, the most frequent causes were non-prion diseases, either untreatable (38%) or potentially treatable (32%), thus leaving sCJD as a less frequent cause (30%). DWI images had a sensitivity of 73% and specificity of 96%, while FLAIR yielded a very low sensitivity (40%). CSF 14-3-3 protein had a sensitivity of 100%, but a very low specificity (43%). The strongest independent predictor of sCJD diagnosis was the CSF tau level (p=0.002) (91% sensitivity, 83% specificity). Treatable causes of RPD are as frequent as sCJD and a rapid differential diagnosis is mandatory. We suggest that DWI images and CSF analysis combining 14-3-3 and total tau protein determination hold the best informative diagnostic values.

Pages 239-262
Benito Minjarez, Ma. Luz Valero Rustarazo, Manuel M. Sanchez del Pino, Arturo González-Robles, Jorge A. Sosa-Melgarejo, Jose Luna-Muñoz, Raul Mena, Juan Pedro Luna-Arias
Identification of Polypeptides in Neurofibrillary Tangles and Total Homogenates of Brains with Alzheimer’s Disease by Tandem Mass Spectrometry
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. AD brains are characterized by the presence of neurofibrillary tangles (NFTs) and neuritic plaques. NFTs are constituted of paired helical filaments, which are structurally composed by assembled hyperphosphorylated and truncated tau polypeptides. To date, the integral constituents of NFTs remain unknown mainly due to the high insolubility of NFTs. The aim of this study was to identify by tandem mass spectrometry, the polypeptides contained in both isolated NFTs by laser capture microdissection and total homogenates, using tissue sections from paraformaldehyde-fixed AD brains. In the first case, we isolated 2,000 NFTs from tissue samples of hippocampus from each of the three Mexican AD brains used in our study. These were previously stained with anti-hyperphosphorylated tau AT-100 antibodies. After the removal of paraformaldehyde and delipidation with organic solvents, we tested three solubilization methods. We identified 102 polypeptides from total homogenates and 41 from isolated NFTs. We selected UCH-L1, transferrin, and GAPDH polypeptides to be studied by immunofluorescence and confocal microscopy. Only UCH-L1 and GAPDH colocalized with hyperphosphorylated tau in NFTs.

Pages 263-271
Maria Teresa Valenti, Silvia Bolognin, Cristina Zanatta, Luca Donatelli, Giulio Innamorati, Maria Pampanin, Gianluigi Zanusso, Paolo Zatta, Luca Dalle Carbonare (Handling Associate Editor: Thomas Bayer)
Increased Glutaminyl Cyclase Expression in Peripheral Blood of Alzheimer’s Disease Patients
Abstract: N-truncated and N-modified forms of amyloid-β (Aβ) peptide are found in diffused and dense core plaques in Alzheimer’s disease (AD) brain. Among them, the most abundant N-truncated peptide starts with pyroglutamyl at residue 3 (AβpE3). AβpE3 has increased aggregation potential and toxicity and its abundance has been reported to correlate with the severity of the clinical phenotype in AD patients. N-terminal glutamate conversion generating AβpE3 is catalyzed by glutaminyl cyclase. This enzyme was found to be upregulated in the cortex of patients with AD. In the present study, we investigated glutaminyl cyclase mRNA and protein expression in peripheral blood from AD patients and age-matched controls. Higher levels of glutaminyl cyclase mRNA and protein were present in AD patients compared with controls. Interestingly, we observed a correlation between glutaminyl cyclase expression and the severity of dementia (value of Mini-Mental State Examination). Therefore, we propose glutaminyl cyclase dosage in peripheral blood as a potential biomarker of AD.

Pages 273-279
Yuriko Katsumata, Hidemi Todoriki, Yasushi Higashiuesato, Shotoku Yasura, Yusuke Ohya, D. Craig Willcox, Hiroko H. Dodge (Handling Associate Editor: Monique Mulder)
Very Old Adults with Better Memory Function have Higher Low-Density Lipoprotein Cholesterol Levels and Lower Triglyceride to High-Density Lipoprotein Cholesterol Ratios: KOCOA Project
Abstract: We cross-sectionally examined which lipid profiles are associated with better cognitive function among those aged 80 and older, free of dementia (Clinical Dementia Rating ≤ 0.5), functionally independent, and community-dwelling. Our cohort consisted of 193 participants from the “Keys to Optimal Cognitive Aging (KOCOA) Project”, a prospective cohort study in Okinawa, Japan. Higher low-density lipoprotein cholesterol levels and lower triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratios were associated with higher scores in memory performance after controlling for confounders. Further research is required to clarify the associations among LDL-C levels, TG/HDL-C ratios, and healthy cognitive aging.

Pages 281-291
Alma Sanchez, Debjani Tripathy, Jinau Luo, Xiangling Yin, Joseph Martinez, Paula Grammas
Neurovascular Unit and the Effects of Dosage in VEGF Toxicity: Role for Oxidative Stress and Thrombin
Abstract: Bidirectional communication between neurons and vascular cells is important to the maintenance of the central nervous system (CNS) milieu. Vascular endothelial growth factor (VEGF), through its ability to affect both vascular and neuronal cells, is likely a key protein in this process. Despite considerable literature documenting a neuroprotective function for VEGF, overexpression of this protein has also been shown in a wide variety of CNS diseases, including Alzheimer’s disease (AD). Increased oxidative stress and elevated thrombin levels have also been documented in AD, specifically in the microvasculature. The aim of the current study is to examine endothelial cells and neurons in vitro to determine the effects of oxidative stress and thrombin on VEGF release as well as the effects of low and high dose VEGF on neuronal viability. The data show that microvessels isolated from AD patients secrete significantly higher levels of VEGF compared to control-derived vessels. Exposure of brain endothelial cells to oxidative stress (sodium nitroprusside, menadione, or hydrogen peroxide) or thrombin significantly increases VEGF expression. Exposure of cultured neurons to oxidative stress increases expression of thrombin. Treating rat cortical neurons with high dose VEGF (≥ 500 ng/ml) decreases neuronal survival and expression of the anti-apoptotic protein Bcl-2 while increasing proapoptic proteins caspase 3 and phosphorylated p38 MAPK. High dose VEGF also negates the decrease in amyloid-β evoked by low dose VEGF. These results suggest that despite literature supporting neuroprotective effects of this protein, caution is warranted prior to implementation of VEGF as a therapeutic in the brain.

Mini-Forum on Research from French Clinical Centers: From Biology to Social Aspects (Guest Editor: Philippe Robert)

Pages 295-296
Mini-Forum Editorial
Philippe Robert
At the End of a Very Hard Day, People Find Some Reason to Believe

Pages 297-305
Mini-Forum Research Report
Audrey Gabelle*, Julien Dumurgier*, Olivier Vercruysse*, Claire Paquet, Stéphanie Bombois, Jean-Louis Laplanche, Katell Peoc’h, Susanna Schraen, Luc Buée, Florence Pasquier, Jacques Hugon, Jacques Touchon, Sylvain Lehmann *These authors contributed equally to the manuscript.
Impact of the 2008-2012 French Alzheimer Plan on the Use of Cerebrospinal Fluid Biomarkers in Research Memory Center: The PLM Study
Abstract: The French Alzheimer's Disease Plan aims, in an unprecedented national effort, to develop research, promote optimal diagnosis, and take better care of patients. In order to evaluate the clinical interest and use of cerebrospinal fluid (CSF) biomarkers, a data-sharing project, the PLM (Paris-North, Lillem and Montpellier) study has emerged through collaboration between these memory centers, already involved in this field. The revised Alzheimer’s disease (AD) diagnosis criteria include CSF biomarkers, but little is known about their use in routine clinical practice. To evaluate their interest and diagnostic accuracy in routine AD diagnosis, a cohort of 677 patients from Montpellier was first analyzed. The results were then validated through the analysis of a second cohort of 638 patients from Lille and Paris-Nord. Diagnoses of AD and other dementias were established by multidisciplinary expert teams, based on neuropsychological exams and structural brain imaging, blinded from CSF results. CSF amyloid-β, tau, and p-tau concentrations were measured for all patients. Receiver-operating characteristic curves were used to define cut-offs and evaluate the ability of each biomarker to discriminate AD from other diagnoses. We showed that p-tau outperformed other biomarkers for discriminating AD from non-AD patients and presents a clear clinical interest. The other biomarkers also showed relevant variations especially when the differential AD diagnoses were taken into account. Altogether we could demonstrate in both mono-centric and multi-centric cohorts from memory clinics the capacity of CSF biomarkers to discriminate AD from non-AD patients in clinical routine with a high sensitivity and specificity.

Supplementary Data for Gabelle et al. article (PDF)

Pages 307-314
Mini-Forum Review
Clément Pimouguet, Valérie Bassi, Dominique Somme, Benoit Lavallart, Catherine Helmer, Jean François Dartigues
The 2008-2012 French Alzheimer Plan: A Unique Opportunity for Improving Integrated Care for Dementia
Abstract: The 2008-2012 French Alzheimer plan has proposed measures to improve care for dementia patients in a more personalized and graduate approach owing to patients and caregivers needs. A key measure of the plan is the nationwide implementation of the MAIA (French acronym for Maison pour l’Autonomie et l’Intégration des malades d’Alzheimer). The main goal is to implement a process of integration through a network of partners involved in elderly care, assistance, or support. The MAIA model comprises tools and mechanisms necessary to improve the integrated care process; in particular, case management for elderly in complex situations. The purpose of this paper is to describe the main measures from the national plan that aim to improve care for dementia patients with an emphasis on the MAIA measure. We summarize initials results of case management activity in one MAIA in the South West of France and we present two vignettes of cases benefiting from case management in order to demonstrate of what the intervention consists. The French Alzheimer plan has promoted several non-pharmacological strategies for dementia patients. Implementation of both integrated care and case management represent a challenging perspective for the elderly and health professionals.

Pages 315-323
Mini-Forum Research Report
Denys Fontaine, Audrey Deudon, Jean Jacques Lemaire, Micheline Razzouk, Philippe Viau, Jacques Darcourt, Philippe Robert
Symptomatic Treatment of Memory Decline in Alzheimer’s Disease by Deep Brain Stimulation: A Feasibility Study
Abstract: Recent studies have suggested that memory circuits can be modulated by deep brain stimulation (DBS). This propriety might be used to slow down cognitive decline in patients suffering from Alzheimer’s disease (AD). We conducted a prospective study to evaluate the feasibility and safety of DBS in AD patients with mild cognitive decline. Inclusion criteria were: patients (<70 years old) with AD diagnosed for less than 2 years, predominant impairment of episodic memory, and Mini-Mental Status Exam (MMSE) score between 20 and 24. The fornix was stimulated bilaterally by electrodes implanted stereotactically in the hypothalamus. Clinical, biological, neuropsychological, and imaging evaluations were conducted 3 months before surgery and 3, 6, and 12 months thereafter. During the one year-period of inclusion, 110 patients with recently diagnosed AD and predominant impairment of episodic memory were screened. Only 9 patients (8.2%) fulfilled all the inclusion criteria. Finally, just one patient accepted to be operated (acceptance rate 11.1%) and completed the study. No complications occurred and the stimulation was perfectly tolerated. After one year of stimulation, the memory scores (MMSE, ADAS-Cog, Free and Cued Selective Reminding Test) were stabilized compared to baseline, and mesial temporal lobes metabolism increased. This pilot study provides new data about the safety of fornix DBS in the hypothalamus. However, it suggests that only a small proportion of AD patients might be interested in this approach and that the acceptance of DBS by AD patients was low, raising questions about the relevance of this approach to meet the expectations of these patients.

Pages 325-338
Mini-Forum Research Report
Therese Rivasseau Jonveaux, Martine Batt, Reihard Fescharek , Athanase Benetos, Alain Trognon, Stanislas Bah Chuzeville, Alina Pop , Christel Jacob, Manon Yzoard, Laetitia Demarche, Laure Soulon, Gabriel Malerba, Bruno Bouvel (Handling Associate Editor: Sylvie Belleville)
Healing Gardens and Cognitive Behavioral Units in the Management of Alzheimer's Disease Patients: The Nancy Experience
Abstract: The French Alzheimer Plan 2008-2012 anticipates the implementation of new Units specialized in cognitive rehabilitation and psycho-behavioral therapy of Alzheimer’s disease (AD) patients. Conceived for AD and other dementia patients of all ages, their objectives are to propose a cognitive rehabilitation program, to prevent or treat psycho-behavioral crises, and to provide support and educational therapy to the family and professional caregivers, in order to ease the patient’s return to his or her previous way of life. Studies on green spaces and healing gardens in health-care settings have revealed objective and measurable improvements in the patient’s well-being. The Plan officially stipulates for the first time the need to make healing gardens an integral part of these Units, but it does not provide specific recommendations or criteria for implementing such gardens. Although green spaces and gardens are available in many French Care Units, they are rarely specifically adapted to the needs of AD patients. In Nancy, the Art, Memory and Life garden, a specific concept guided by a neuropsychological approach, was developed and complemented by an artistic vision based on cultural invariants. The main objective of this article is to describe the various steps of the process that led to the creation of this garden: the collection of experiences and information by a pilot group, surveys of patients, visitors, and caregivers before and after establishment of the garden, and implementation of a multi-professional group project. The specifications, the organizational criteria, the therapeutic project, and the criteria for the conception of such a garden stemming from our clinical experience with the Art, Memory and Life garden in Nancy, are described herein. We also present the first assessment following the implementation of the project.

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