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The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Funder: QingLan Research Project of Jiangsu for Outstanding Young Teachers, Funder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, Funder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University, We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

ATENCIÓ: la correcció està també al DDD, cal relacionar??? https://ddd.uab.cat/record/226203 Altres ajuts: The following studies and consortia have contributed to this manuscript. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe): This study/publication is part of the German Research Network on Dementia (KND), the German Research Network on Degenerative Dementia (KNDD; German Study on Ageing, Cognition and Dementia in Primary Care Patients; AgeCoDe), and the Health Service Research Initiative (Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+; AgeQualiDe)) and was funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716; grants Health Service Research Initiative: 01GY1322A, 01GY1322B, 01GY1322C, 01GY1322D, 01GY1322E, 01GY1322F, 01GY1322G). Alfredo Ramirez was partly supported by the ADAPTED consortium: Alzheimer's disease Apolipoprotein Pathology for Treatment Elucidation and Development, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. Brain compendium: This work was funded by the UK Medical Research Council (13044). P.F.C. is a Wellcome Trust principal Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.Clinical AD, Sweden: We would like to thank UCL Genomics for performing the genotyping analyses. Danish data: The studies behind the Danish long-lived cases received funding from The National Program for Research Infrastructure 2007 (grant no. 09-063256), the Danish Agency for Science Technology and Innovation, the Velux Foundation, the US National Institute of Health (P01 AG08761), the Danish Agency for Science, Technology and Innovation/The Danish Council for Independent Research (grant no. 11-107308), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the CERA Foundation (Lyon), the AXA Research Fund, Paris, and The Health Foundation (Helsefonden), Copenhagen, Denmark. The GOYA study was conducted as part of the activities of the Danish Obesity Research Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth Cohort which was established with major funding from the Danish National Research Foundation. Additional support for this cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Fundació ACE (FACE): We would like to thank patients and controls who participated in this project. We are indebted to Trinitat Port-Carbó and her family for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). Agustín Ruiz has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED Grant No. 115975 and by grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- "Una manera de Hacer Europa"), by Fundación bancaria "La Caixa" and Grifols SA (GR@ACE project). Genetics of Healthy Ageing Study (GEHA - NL): The work described in this paper was funded mainly by the EU GEHA Project contract no. LSHM-CT-2004-503-270. Gothenburg Birth Cohort (GBC) Studies: We would like to thank UCL Genomics for performing the genotyping analyses. The studies were supported by The Stena Foundation, The Swedish Research Council (2015-02830, 2013-8717), The Swedish Research Council for Health, Working Life and Wellfare (2013-1202, 2005-0762, 2008-1210, 2013-2300, 2013-2496, 2013-0475), The Brain Foundation, Sahlgrenska University Hospital (ALF), The Alzheimer's Association (IIRG-03-6168), The Alzheimer's Association Zenith Award (ZEN-01-3151), Eivind och Elsa K:son Sylvans Stiftelse, The Swedish Alzheimer Foundation. International FTD-Genomics Consortium (IFGC): International FTD-Genomics Consortium (IFGC): The authors thank the IFGC for providing relevant data to support the analyses presented in this manuscript. Further acknowledgments for IFGC (https://ifgcsite.wordpress.com/), e.g. full members list and affiliations, are found in the online supplementary files. IPDGC (​The International Parkinson Disease Genomics Consortium): We also would like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). See for a complete overview of members, acknowledgements and funding http://pdgenetics.org/partners. Kompetenznetz Multiple Sklerose (KKNMS): This work was supported by the German Ministry for Education and Research (BMBF) as part of the "German Competence Network Multiple Sclerosis" (KKNMS) (grant nos. 01GI0916 and 01GI0917) and the Munich Cluster for Systems Neurology (SyNergy). TA was supported by the BMBF through the Integrated Network IntegraMent, under the auspices of the e:Med Programme (01ZX1614J). BH was supported by the EU Horizon 2020 project MultipleMS.Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. Leiden Longevity Study: This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (Grant 050-060-810), all in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and by Unilever Colworth.Maria Carolina Dalmasso: Georg Forster Research Award (Alexander von Humboldt Foundation). Mayo Clinic AD, DLB, PD, PSP: We thank the patients and their families for their participation, without whom these studies would not have been possible. Funding for this work was supported by National Institute on Aging [RF AG051504 to NET.; U01 AG046139 to NET]; and National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET; P50 NS072187]. The Mayo Clinic is a Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Information and Referral Center and Center for Advanced Research, NINDS Tau Center without Walls (U54-NS100693) and is supported by Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, the Mangurian Foundation for Lewy body research and NINDS R01 NS078086 (to OAR). The PD program at the Mayo Clinic Florida is also supported by the Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, and The Sol Goldman Charitable Trust. Samples included in this study are from the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP The online version of this article (10.1007/s00401-019-02026-8) contains supplementary material, which is available to authorized users.

Les benefices therapeutiques des traitements disposant de l’AMM depuis plus de 15 ans dans la MA, qu’il s’agisse des anticholinesterasiques et ou de la memantine, sont modestes mais reels, confirmes par les etudes en double aveugle contre placebo ou par la comparaison avec l’evolution naturelle de la maladie. L’efficacite des inhibiteurs des cholinesterases (IchE) et de la memantine a ete mesuree sur 4 dimensions de la maladie : la cognition, les activites de vie quotidienne, les troubles de l’humeur et du comportement, et l’impression globale de changement. L’objectif de cet article est double : 1) aborder les conditions dans lesquelles ces traitements symptomatiques sont prescrits en France au travers d’une enquete nationale menee par la federation nationale des CMRR ; 2) examiner les donnees actuellement disponibles concernant leur efficacite, leur tolerance, leur impact medico-economique, ainsi que les positions des autorites sanitaires sur les conditions de leur prescription, dans les autres pays europeens.

Resume Contexte Les criteres du diagnostic clinique de maladie d’Alzheimer (MA) ont ete etablis en 1984. L’evolution des connaissances rendait indispensable leur revision. Methodes Le National Institute on Aging (NIA) et l’Alzheimer's Association (AA) ont commissionne trois groupes d’experts pour etablir de nouveaux criteres de MA destines a la clinique et a la recherche. Apres avoir revu les donnees scientifiques actuelles concernant l’epidemiologie, la neuropsychologie et les biomarqueurs, les experts ont propose un cadre conceptuel de reflexion ainsi que des criteres de recherche operationnels. Resultats Trois stades precliniques de MA ont ete proposes : amyloidose cerebrale asymptomatique, amyloidose cerebrale asymptomatique + neurodegenerescence, et amyloidose cerebrale + neurodegenerescence + declin cognitif minime. Le groupe a developpe des recommandations afin de determiner les facteurs predictifs du risque de progression de la cognition normale au mild cognitive impairment (MCI) et a la demence due a la MA. Il est necessaire de clarifier ces modeles au moyen d’etudes cliniques longitudinales. Les groupes sur le MCI et la demence dus a la MA ont developpe des criteres cliniques suffisamment flexibles pour etre utilisables par les cliniciens sans moyens neuropsychologiques et qui ne disposent pas d’imagerie sophistiquee ni d’analyse du liquide cephalorachidien (LCR), mais egalement par les chercheurs impliques dans la recherche clinique et les essais therapeutiques lorsque ceux-ci disposent de l’imagerie et des biomarqueurs du LCR. La phase symptomatique predementielle de la MA est designee sous le terme de MCI du a la MA. Des criteres cardinaux cliniques et cognitifs du MCI ont ete proposes, et quatre niveaux de certitude du MCI du a la MA ont ete definis en fonction de la presence et de la nature des biomarqueurs. Des criteres generaux de demence et de demence due a la MA ont ete definis. La demence due a la MA a ete classee en : demence due a la MA probable, demence due a la MA possible, et demence due a la MA probable ou possible avec preuve du processus physiopathologique de la MA, a utiliser pour la recherche. Les criteres cliniques cardinaux de demence due a la MA continueront a etre la pierre angulaire du diagnostic en pratique clinique courante, mais les biomarqueurs sont censes ameliorer la specificite du diagnostic physiopathologique. Conclusions Dans ces nouveaux criteres, une distinction conceptuelle est faite entre le processus physiopathologique de la MA et les syndromes cliniques qui en resultent. Les criteres cliniques cardinaux concernant le MCI et la demence dus a la MA ont pour objectif de guider le diagnostic en pratique clinique alors que les recommandations sur les stades precliniques sont destinees a la recherche et n’ont aucune implication clinique. Un travail considerable reste necessaire pour valider l’utilisation des biomarqueurs dans ces criteres et pour standardiser leur utilisation en pratique courante.

The objective of this study was to examine the diagnostic accuracy of imaging and CSF biomarkers in clinically ambiguous dementia (CAD). 69 patients were prospectively followed. The endpoint was clinical diagnosis at follow-up of 24 months based upon existing criteria. Medial temporal lobe atrophy score on MRI, distinctive patterns on 99 mTc-HMPAO- SPECT, and CSF levels of amyloid- peptide, total tau protein, and P-tau181P were used together with neuropsychological testing to assess Se (sensitivity) and Sp (specificity) of separate and combined markers. 60 patients reached the endpoint. A definite diagnosis was achieved in 48 patients. CSF biomarkers had a Sp of 71% and a Se of 100% for Alzheimer's disease (AD) diagnosis. Sp increased to 88% and 93% when MRI and MRI + SPECT were combined, at the expense of Se. CSF biomarkers levels also provided clues to frontotemporal (FTD) or vascular dementias (VaD) diagnosis when situated in an intermediate range between normal and pathological values. MRI and SPECT contributed mostly to the diagnosis of VaD (Se 88%, Sp 75%) and FTD (Se 73%, Sp 78%), respectively. Initial neuropsychological testing had a poor diagnostic accuracy, except for a neuropsychiatric inventory score >40 for the diagnosis of FTD (Se 73%, Sp 84%). Independent of the clinical diagnosis, medial temporal lobe atrophy and total-tau were best correlated with cognitive decline at 2 years. In conclusion, CSF biomarkers efficiently predict evolution toward an AD phenotype in CAD. Imaging biomarkers mostly contribute to the differential diagnosis between non-AD dementias. Initial neuropsychological testing was poorly contributive in CAD diagnosis.

The study evaluated the impact of a general practice-based intervention on 3021 patients in France aged 75 years and above with spontaneous memory complaints. The objective was to identify evocative signs of Alzheimer's disease through a cluster randomized controlled trial. The study involved 681 general practitioners (GPs), randomly selected and assigned to an intervention ( n = 352) or a control group ( n = 329), and 214 specialists. The intervention group participated in training sessions relating to dementia diagnosis and the use of brief neuropsychological tests suited to general practice. The control group dispensed usual general practitioner care. The primary outcome was suspicion of dementia by GPs. The secondary outcome was accurate detection of dementia by the GPs. Most patients (96%) were already followed by the GPs (mean follow-up duration 10.8 years, similar in both groups). Suspicion of dementia was two-fold higher for GPs in the intervention group (adjusted OR = 1.99, p < 0.0001). Probability of suspected dementia increased with patient age and decreased with educational level. However the positive predictive value was not significantly different between the two groups (60.9% vs. 64.4%, p = 0.41). GPs from the intervention group also had a higher probability (adjusted OR = 2.24, p = 0.01) of correctly detecting demented patients (intervention did not increase the number of diagnosed cases of dementia, but increased the number of suspected cases that were later confirmed by specialists). The study showed that information on dementia and application of simple psychometric tests could improve the precision of a GP's diagnosis without changing the efficacy of detection of dementia.

TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. We identified 5 LoF mutations, in 4 FTD-ALS and 1 ALS patients. We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.

Very few studies on the neurotransmitter systems involved in frontotemporal dementia (FTD) have been published. No cholinergic deficiency is associated with FTD. Correlating non-specific, serotoninergic dysfunction and behavioral disorders permitted developing clinical trials on selective serotonin reuptake inhibitors (SSRIs). All five trials included a limited number of patients. Two preliminary trials involving the treatment of cognitive and attentional dysfunctions by noradrenergic agents were also developed on the hypothesis that noradrenergic system dysfunction was associated with FTD. Replacement neurotransmitter therapy to treat behavioral and cognitive symptoms in FTD has, however, proved disappointing so far. The pathophysiology of FTD is still poorly understood. Abnormalities linked to the tau protein level and excitotoxicity have been hypothesised. The most promising biological therapy would currently be to inhibit tau protein aggregation. Developing clinical trials on neuroprotective drugs will therefore require prior development of rating scales specific to this essentially behavioral type of dementia.

Neurodegenerative diseases and, in particular, Alzheimer disease, are characterized by progressive neuronal loss correlated in time with the symptoms of the disease considered. Whereas the symptoms of those incapacitating diseases are beginning to be managed with a relative efficacy, the ultimate objective of therapy nonetheless remains preventing cell (neuronal and/or astrocytic) death in a neurocytoprotective approach. In biologic terms, in the light of progress at basic research level, three strategies may be envisaged: (1) antagonizing the cytotoxic causal events (excess intracellular calcium, accumulation of abnormal proteins, excitotoxic effects of amino acids, oxidative stress, processes related to inflammation, etc.); (2) stimulating the endogenous protective processes (anti-free radical or DNA repair systems, production of neurotrophic factors, potential cytoprotective action of steroids, etc.); (3) promoting damaged structure repair strategies (grafts) or deep brain or cortical neurostimulation with a view to triggering (beyond the symptomatic actions) potential 'protective' cell mechanisms. The clinical transition of the various strategies whose efficacy is being tested in animal and/or cell models, experimental analogs of the diseases, and thus the objective demonstration in humans of pharmacological and/or surgical neurocytoprotection, is currently the subject of considerable methodological debate (What are the right psychometric assessment criteria? What are the most pertinent laboratory or neuroradiological markers, etc.?). A number of clinical trials have been completed or are ongoing with drugs that are reputed to be neuroprotective. Thus, elements of the response are beginning to be generated with a view to determining whether it will soon be possible to effectively slow or even stop the neurodegenerative process whose etiology, in most cases, remains obscure.

Resume Les fistules durales sont des communications arterio-veineuses developpees dans l’epaisseur de la dure-mere se revelant habituellement par des acouphenes ou des hemorragies intracerebrales. Leur pronostic depend du type de drainage veineux de la fistule. Nous rapportons les observations de deux femmes presentant une deterioration cognitive progressive evoluant rapidement vers un syndrome dementiel. L’arteriographie cerebrale mit en evidence une fistule durale se drainant a contre courant dans les veines corticales. Une embolisation par abord trans-osseux permit l’occlusion des fistules et entraina une amelioration spectaculaire et durable de l’etat clinique de ces patientes. Les fistules durales a drainage veineux cortical peuvent etre a l’origine d’un syndrome dementiel traduisant une encephalopathie par hyperpression veineuse. L’embolisation des afferences arterielles, souvent multiples, est le traitement habituel, mais parfois insuffisant. En cas d’occlusion des voies de drainage sinusiennes normales, l’abord trans-osseux est alors la seule option permettant la cure de la fistule et la regression du syndrome dementiel.

sequence (n1⁄423), were evaluated on the Saykin scale modified for severity (Saykin-mod-sev), (Saykin, Reisberg modification, 2013), and an Emotional Severity Scale (ESS), (Guillo BenArous, 2013). We compared the scales with respect to scores on a battery of psychological tests and demographic variables, specifically, age, gender, and education. Results: We found a significant relationship between the Saykin ADNI Self Report Index and the Trail Making Test B (P1⁄40.009) (see figure). We also found a significant relationship between the Visual Analogue Scale and the Paired Associates Delayed Recall measure (p1⁄40.028). For the demographic variables a significant relationship was found with selected tests (see Figure). Conclusions: These findings could be of relevance for future prevention trials. Ultimately, we need to determine the sensitivity of temporally based scales in comparison with severity based scales and identify optimal predictors of eventual MCI and AD.

The behavioral variant of frontotemporal dementia (bvFTD), characterized by early behavioral disorders, is a rare disease (about 5.000 cases in France). Diagnostic criteria have been revised in 2011 and propose three levels of diagnostic probability. However, it still could be difficult to discriminate FTD from other cerebral affections or psychiatric diseases. Genetic and molecular research has greatly expanded during the past fifteen years. About ten mutations have been discovered, bringing to describe particular phenotypes. To date, there is no curative treatment. Memantine had aroused some hope but is now abandoned. Inhibitors of serotonine recapture often permit to temporarily reduce behavioral troubles. But the caregiver's burden is high. The evolution of the bvFTD is faster than that of AD, particularly when associated with motor neuron disease (15% of cases). The therapeutic hope relies today on potential disease modifying drugs which could ensue from genetic discoveries.

By definition, anxiolytics are drugs capable of treating anxiety and anxiety related disorders. The precise role of anxiolytics, particularly in comparison with other drug classes (e.g., antipsychotics and antidepressants) and other therapeutic approaches (e.g., psychotherapy, behavioral therapy, and relaxation) in treating behavioral and psychological symptoms of dementia (BPSD) needs to be determined. If anxiolytics are used for BPSD, the clinician must decide whether they should be used as an emergency measure, as long-term therapy, or both. Also, whether anxiolytics are useful in treating anxiety and its consequences in both the early and advanced stages of dementia must be considered.

Between 1993 and 1995, we observed five sporadic cases of frontotemporal dementia (FTD) which in all cases preceded the appearance of typical amyotrophic lateral sclerosis (ALS). The FTD rapidly became severe (within 12-18 months) and the delay between the presumed onset of mental change and ALS was short (12-26 months). The frontal dysfunction was characteristic (disinhibited, jocular, impatient, gluttonous, stereotypical gestures). The language impairment (less talkative, persistent errors, fantastic and semantic paraphasia, neologistic errors, echolalia) was constant. Single photon emission computed tomography (SPECT) with 99 Tcm HMPAO (hexamethyl propylamine oxime) was done at the same time as neuropsychological testing in four cases and showed serious diffuse bifrontal defect, sometimes with less serious internal temporal hypofixation. All patients died with bulbar ALS complications. The total course can last from 14-48 months. Most of the reported cases suggested a relationship between dementia-ALS and frontal dysfunction. The mechanism underlying dementia-ALS remains to be solved. Our five cases resemble those reported by Mitsuyama (1993), who suggested that dementia-ALS has the same clinicopathological entity.

International audience; La démence à corps de Lewy (DCL) est la deuxième cause de démence dégénérative du sujet âgé, dans les grandes séries autopsiques. Dans la réalité quotidienne des centres mémoire pourtant, la DCL représente une faible proportion des diagnostics cliniques, avec une forte disparité entre les centres. Plusieurs raisons peuvent rendre compte de la faible sensibilité du diagnostic de DCL : l’imprécision et la subjectivité des critères diagnostiques existants ; la place insuffisante donnée à certains signes non-moteurs (troubles du comportement en sommeil paradoxal, dysautonomie) ; enfin et surtout l’association quasi constante de la pathologie de Lewy à une pathologie de type Alzheimer, qui domine rapidement le phénotype clinique. À l’heure de l’essor des thérapies ciblées contre les agrégats protéiques, de nouvelles échelles cliniques permettant d’appréhender la coexistence de la pathologie de Lewy dans la maladie d’Alzheimer sont plus que jamais nécessaires.

The first case of Creutzfeldt-Jakob disease (CJD) related to the use of a dura mater graft of cadaveric origin was identified in 1987 and this procedure is now considered as one of the main causes of iatrogenic CJD. Although the decontamination procedure for the preparation of graft material was modified, the product was withdrawn from the market in many countries a few years later and replaced by synthetic material. In this context, two patients treated in our institution developed CJD following a cadaveric dural graft performed after cerebral and lumbar trauma. Their clinical presentation, showing predominant cerebellar symptoms, late deterioration and myoclonic jerks, and a rapid disease course until death, was similar to that of previously reported cases involving the iatrogenic form. As the graft for one of the patients was performed in 1991 (several years after modification of the decontamination procedure), this fourth reported case suggests that the risk of iatrogenic CJD may have persisted in some patients treated after 1987, when grafts of cadaveric origin were totally abandoned.

Background: Male carriers of the FMR1 premutation are at risk of developing the fragile X-associated tremor/ataxia syndrome (FXTAS), a newly recognized and largely under-diagnosed late onset neurodegenerative disorder. Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor. Cognitive decline has also been associated with the premutation but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counseling. Methods: The Mattis Dementia Rating Scale (MDRS) was administered in a double-blind fashion to 74 males aged 50 years or more recruited from fragile X families (35 premutation carriers and 39 intrafamilial controls) regardless of their clinical manifestation. Based on previous publications, marked cognitive impairment was defined by a score ≤ 123 on the MDRS. Results: Both logistic and survival models confirmed that in addition to age and education level, premutation size plays a significant (p

Objective: To evaluate the frequency of c9ORF72 repeat expansion in french FTLD and FTLD-ALS patients and to describe the associated clinical phenotypes, imaging and brain pathological characteristics. Background c9ORF72 was recently identified as a major gene implicated in FTLD/ALS spectrum of disease. Its genetic contribution remains to be established in different geographic populations. Design/Methods: c9ORF72 repeat expansion was searched for by repeat-primed PCR in 600 french probands with frontal variant FTD (fvFTD, n=330), FTLD with amyotrophic lateral scelrosis (FTLD-ALS, n=210), primary progressive aphasia (PPA, n=40) and progressive supranuclear palsy (PSP, n=20). Half patients had a family history of FTLD or ALS, half were sporadic cases. Brain post-mortem examination was performed in 18 patients. Results: A GGGGCC repeat expansion was identified in 140 unrelated probands. The frequency of the expansion was 15% in the patients with bvFTD (8% in sporadic cases, 20% in familial bvFTD)and 43% in the patients with FTLD-ALS (15% in sporadic cases; 64% in familial forms). No expansion was identified in the PPA patients. Most patients had a bvFTD; only two patients presented with semantic dementia or progressive non fluent aphasia both associated with ALS at onset. The detailed clinical phenotypes, SPECT imaging characteristics and pathology of 60 c9ORF72 expansion carriers will be presented. Conclusions: c9ORF gene is the most frequent cause of familial FTLD before PGRN gene. The frequency of mutation is much higher in the population with FTLD-ALS. Less than 30% of familial FTLD/FTLD-ALS are unexplained by the eight known FTLD genes. Disclosure: Dr. Le Ber has nothing to disclose. Dr. Camuzat has nothing to disclose. Dr. Guillot-Noel has nothing to disclose. Dr. Guedj has nothing to disclose. Dr. Hannequin has nothing to disclose. Dr. Wargon has nothing to disclose. Dr. Couratier has nothing to disclose. Dr. Deramecourt has nothing to disclose. Dr. Berger has nothing to disclose. Dr. Viennet has nothing to disclose. Dr. Pasquier has nothing to disclose. Dr. Lacomblez Aurousseau has nothing to disclose. Dr. Salachas has nothing to disclose. Dr. Martinaud has nothing to disclose. Dr. Golfier has nothing to disclose. Dr. Puel has nothing to disclose. Dr. Vercelletto has nothing to disclose. Dr. Didic has nothing to disclose. Dr. Sauvee has nothing to disclose. Dr. Sellal has nothing to disclose. Dr. Thomas-Anterion has nothing to disclose. Dr. Campion has nothing to disclose. Dr. Michel has nothing to disclose. Dr. Dubois has received personal compensation for activities with Bristol-Myers Squibb, Roche, Elan, Eli Lilly, Eisai, and Janssen as a consultantDr. Dubois has received personal compensation for serving on the advisory board of Bristol-Myers Squibb, Roche, Elan, Eli Lilly, Eisai, and Janssen.Dr. Dubois has received research support from Novartis and Sanofi-Aventis. Dr. Camu has nothing to disclose. Dr. Seilhean has nothing to disclose. Dr. Meininger has received personal compensation for activities with Servier and GlaxoSmithKline. Dr. Habert has nothing to disclose. Dr. Duyckaerts has nothing to disclose. Dr. Brice has nothing to disclose.