Publications by authors named "Martine Vercelletto"

32 Publications

Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers.

Neurobiol Aging 2019 02 19;74:234.e1-234.e8. Epub 2018 Sep 19.

Assistance Publique - Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et la Moelle épinière ICM, Hôpital Pitié-Salpêtrière, Paris, France; National Reference Center for Rare or Early Dementias, Institute of Memory and Alzheimer's Disease IM2A, Department of Neurology, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France. Electronic address:

A (GGGGCC) repeat expansion in C9orf72 gene is the major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The relations between the repeats size and the age at disease onset (AO) or the clinical phenotype (FTD vs. ALS) were investigated in 125 FTD, ALS, and presymptomatic carriers. Positive correlations were found between repeats number and the AO (p < 10) but our results suggested that the association was mainly driven by age at collection (p < 10). A weaker association was observed with clinical presentation (p = 0.02), which became nonsignificant after adjustment for the age at collection in each group. Importantly, repeats number variably expanded or contracted over time in carriers with multiple blood samples, as well as through generations in parent-offspring pairs, conversely to what occurs in several expansion diseases with anticipation at the molecular level. Finally, this study establishes that measure of repeats number in lymphocytes is not a reliable biomarker predictive of the AO or disease outcome in C9orf72 long expansion carriers.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.09.010DOI Listing
February 2019

Author Correction: Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates.

Sci Rep 2018 Mar 1;8(1):4064. Epub 2018 Mar 1.

Department of Molecular Neuroscience, UCL Institute of Neurology Queen Square, London, WC1N 3BG, UK.

A correction has been published and is linked to the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-22152-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832856PMC
March 2018

Cerebral microbleeds and CSF Alzheimer biomarkers in primary progressive aphasias.

Neurology 2018 03 14;90(12):e1057-e1065. Epub 2018 Feb 14.

From the Department of Internal Medicine, Rehabilitation and Geriatrics (A.M.), Geneva University Hospitals and University of Geneva, Switzerland; Department of Neurology (A.M., S.E., B.D., M.T.), National Reference Center for PPA and Rare Dementias, Institute for Memory and Alzheimer's Disease, Pitié Salpêtrière Hospital, AP-HP, Paris; Sorbonne Universités (A.B., O.C., A.R., S.E., L.F., M.C., B.D., M.T.), UPMC University Paris 06, Inserm, CNRS, Institut du Cerveau et la Moelle, Paris; Inria Paris (A.B., O.C., A.R., S.E., T.K.), Aramis Project-Team, Paris; Departments of Neuroradiology (A.B.) and Metabolic Biochemistry (F.L.), Pitié Salpêtrière Hospital, AP-HP, Paris; Department of Neurology and Laboratory of Functional Neurosciences (EA 4559) (O.G.), University Hospital of Amiens; Department of Neurology (F.E.-B.), Memory Research and Resource Center for Alzheimer's Disease, University Hospital of Angers; Department of Psychiatry, Neurology and Rehabilitation (O. Moreaud), University Hospital of Grenoble, Memory Research and Resource Center for Alzheimer's Disease; Department of Neurology (F.P.), University Hospital of Lille; Department of Neurology (P.C.), University Hospital of Limoges; Department of Neurology (K.B.), Memory Research and Resource Center for Alzheimer's Disease, University Hospital of Montpellier; Department of Neurology (M.V.), University Hospital of Nantes; Department of Neurology (O. Martinaud), University Hospital of Rouen; Normandie University (O. Martinaud, S.B.), UNICAEN, EPHE, INSERM, U1077, Neuropsychologie et Imagerie de la Mémoire Humaine; Department of Neurology (B.L.), University Hospital of Saint-Etienne; Department of Neurology (J.P., M.P.), Pierre Paul Riquet Hospital, Toulouse; INSERM/UPS (J.P.), UMR 1214-ToNIC, Toulouse NeuroImaging Center, University of Toulouse III; and Department of Neurology (S.B.), Memory Research and Resource Center for Alzheimer's Disease, University Hospital Pontchaillou, Rennes, France.

Objective: To reveal the prevalence and localization of cerebral microbleeds (CMBs) in the 3 main variants of primary progressive aphasia (PPA) (logopenic, semantic, and nonfluent/agrammatic), to identify the relationship with underlying Alzheimer pathology, and to explore whether CMBs contribute to language breakdown.

Methods: We used a cross-sectional design in a multicenter cohort of 82 patients with PPA and 19 similarly aged healthy controls. MRI allowed for rating CMBs (2-dimensional gradient recalled echo T2*, susceptibility weighted imaging sequences) and white matter hyperintensities. CSF Alzheimer disease biomarker analyses available in 63 of the 82 patients provided the stratification of PPA into subgroups with patients who had or did not have probable underlying Alzheimer pathology.

Results: The prevalence of CMBs was higher in patients with PPA (28%) than in controls (16%). They were more prevalent in logopenic PPA (50%) than in semantic PPA (18%) and nonfluent/agrammatic PPA (17%). The localization of CMBs was mainly lobar (81%) with no difference between the PPA variants. CMBs were more frequent in PPA patients with positive than with negative CSF Alzheimer disease biomarkers (67% vs 20%). Patients with and without lobar CMBs had similar volumes of white matter hyperintensities. Language and general cognitive impairment in PPA was unrelated to CMB rates.

Conclusions: CMB prevalence in PPA is higher than in healthy controls. CMBs were most prevalent in the logopenic variant, were related to underlying Alzheimer pathology, and did not affect the language/cognitive impairment. Our findings also suggest that CMB detection with MRI contributes to PPA variant diagnosis, especially of logopenic PPA, and provides an estimator of the underlying neuropathology.
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http://dx.doi.org/10.1212/WNL.0000000000005165DOI Listing
March 2018

Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates.

Sci Rep 2017 05 10;7(1):1666. Epub 2017 May 10.

Department of Molecular Neuroscience, UCL Institute of Neurology Queen Square, London, WC1N 3BG, UK.

Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD continuum. In this work the role of p62 in energy metabolism was studied in fibroblasts from FTD patients carrying two independent pathogenic mutations in the p62 gene, and in a p62-knock-down (p62 KD) human dopaminergic neuroblastoma cell line (SH-SY5Y). We found that p62 deficiency is associated with inhibited complex I mitochondrial respiration due to lack of NADH for the electron transport chain. This deficiency was also associated with increased levels of NADPH reflecting a higher activation of pentose phosphate pathway as this is accompanied with higher cytosolic reduced glutathione (GSH) levels. Complex I inhibition resulted in lower mitochondrial membrane potential and higher cytosolic ROS production. Pharmacological activation of transcription factor Nrf2 increased mitochondrial NADH levels and restored mitochondrial membrane potential in p62-deficient cells. Our results suggest that the phenotype is caused by a loss-of-function effect, because similar alterations were found both in the mutant fibroblasts and the p62 KD model. These findings highlight the implication of energy metabolism in pathophysiological events associated with p62 deficiency.
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http://dx.doi.org/10.1038/s41598-017-01678-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431917PMC
May 2017

Symptomatic treatments in Alzheimer's disease in 2016: a study from Memory centers in France.

Geriatr Psychol Neuropsychiatr Vieil 2016 Sep;14(3):274-86

CMRR PACA, CHU Marseille, France.

Cholinesterase inhibitors and memantine are used from 15 years, in Alzheimer's disease. Benefits have been demonstrated according to cognition, activities of daily living, affective symptoms and behavior, and global impression of change. The aims of this paper are: 1) to describe how these treatments are used in France with a sample survey managed by the national federation of the french CMRR; 2) to study data about efficacy, safety, medicoeconomic impacts and how they are used in Europe.
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http://dx.doi.org/10.1684/pnv.2016.0629DOI Listing
September 2016

Ugly aesthetic perception associated with emotional changes in experience of art by behavioural variant of frontotemporal dementia patients.

Neuropsychologia 2016 08 2;89:96-104. Epub 2016 Jun 2.

Laboratoire d'études des mécanismes cognitifs, EA 3082, Université Lyon 2, Bron F-69500, France; Plein ciel, 75, Rue Bataille, 69008 Lyon, France.

The aesthetic experience through art is a window into the study of emotions. Patients with behavioural variant of frontotemporal dementia (bvFTD) have early alteration of emotional processing. A new appreciation of art has been reported in some of these patients. We designed a computerized task using 32 abstract paintings that allowed us to investigate the integrity of patients' emotions when viewing the artwork. We evaluated both conscious and explicit appraisal of emotions [aesthetic judgment (beautiful/ugly), emotional relevance (affected or not by the painting), emotional valence (pleasant/unpleasant), emotional reaction (adjective choice) and arousal] and unconscious processing. Fifteen bvFTD patients and 15 healthy controls were included. BvFTD patients reported that they were "little touched" by the paintings. Aesthetic judgment was very different between the two groups: the paintings were considered ugly (negative aesthetic bias) and unpleasant (negative emotional bias) more often by the patients than by controls. Valence and aesthetic judgments correlated in both groups. In addition, there was a positive bias in the implicit task and for explicit emotional responses. Patients frequently chose the word "sad" and rarely expressed themselves with such adjectives as "happy". Our results suggest that bvFTD patients can give an aesthetic judgment, but present abstraction difficulties, as spectators, resulting from impairments in the cognitive processes involved. They also have difficulties in terms of emotional processes with the loss of the ability to feel the emotion per se (i.e., to feel an emotion faced with art) linked to behaviour assessment. This cognitive approach allows us to better understand which spectators are bvFTD patients and to show interactions between emotions and behavioural disorders.
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http://dx.doi.org/10.1016/j.neuropsychologia.2016.06.001DOI Listing
August 2016

DAPHNE: A New Tool for the Assessment of the Behavioral Variant of Frontotemporal Dementia.

Dement Geriatr Cogn Dis Extra 2015 Sep-Dec;5(3):503-16. Epub 2015 Dec 18.

Laboratoire d'Etudes des Mécanismes Cognitifs, EA 3082, Université Lyon 2, Bron, Lyon, France; Plein-Ciel, Lyon, France.

Background: The diagnosis of behavioral variant of frontotemporal dementia (bvFTD) relies primarily on clinical features and remains challenging. The specificity of the recently revised criteria can be disappointing, justifying development of new clinical tools.

Objective: We produced a behavioral inventory named DAPHNE. This scale (adapted from Rascovsky's criteria) explores six domains: disinhibition, apathy, perseverations, hyperorality, personal neglect and loss of empathy. It is composed of ten items (five answer categories). The aim was (1) to assess the validity and reliability of DAPHNE and (2) to evaluate its contribution in differentiating patients.

Methods: Two scores were computed: DAPHNE-6 (screening) from the six domains and DAPHNE-40 (diagnosis) from the ten items. Reliability and reproducibility were assessed. External validity was studied with the Frontal Behavioral Inventory (FBI) and the Frontotemporal Behavioral Scale (FBS). Finally, the diagnostic performance of DAPHNE was compared to revised criteria, FBI and FBS.

Results: DAPHNE was administered to the caregivers of 89 patients, 36 with bvFTD, 22 with Alzheimer's disease, 15 with progressive supranuclear palsy and 16 with bipolar disorder. Reliability and reproducibility were excellent, as was external validity. DAPHNE-6 allowed bvFTD diagnosis (score ≥4) with a sensitivity of 92%, while DAPHNE-40 (score ≥15) had a specificity of 92%.

Conclusion: We demonstrate excellent psychometric features for DAPHNE. This quick tool could help for both diagnosing and screening bvFTD.
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http://dx.doi.org/10.1159/000440859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777961PMC
March 2016

The Behavioral and Cognitive Executive Disorders of Stroke: The GREFEX Study.

PLoS One 2016 29;11(1):e0147602. Epub 2016 Jan 29.

Department of Neurology and Laboratory of Functional Neurosciences EA 4559, SFR CAP-Santé (FED 4231), University Hospital of Amiens, Amiens, France.

Background: Many studies have highlighted the high prevalence of executive disorders in stroke. However, major uncertainties remain due to use of variable and non-validated methods. The objectives of this study were: 1) to characterize the executive disorder profile in stroke using a standardized battery, validated diagnosis criteria of executive disorders and validated framework for the interpretation of neuropsychological data and 2) examine the sensitivity of the harmonization standards protocol proposed by the National Institute of Neurological Disorders and Stroke and Canadian Stroke Network (NINDS-CSN) for the diagnosis of Vascular Cognitive Impairment.

Methods: 237 patients (infarct: 57; cerebral hemorrhage: 54; ruptured aneurysm of the anterior communicating artery (ACoA): 80; cerebral venous thrombosis (CVT): 46) were examined by using the GREFEX battery. The patients' test results were interpreted with a validated framework derived from normative data from 780 controls.

Results: Dysexecutive syndrome was observed in 88 (55.7%; 95%CI: 48-63.4) out of the 156 patients with full cognitive and behavioral data: 40 (45.5%) had combined behavioral and cognitive syndromes, 29 (33%) had a behavioral disorder alone and 19 (21.6%) had a cognitive syndrome alone. The dysexecutive profile was characterized by prominent impairments of initiation and generation in the cognitive domain and by hypoactivity with disinterest and anticipation loss in the behavioral domain. Cognitive impairment was more frequent (p = 0.014) in hemorrhage and behavioral disorders were more frequent (p = 0.004) in infarct and hemorrhage. The harmonization standards protocol underestimated (p = 0.007) executive disorders in CVT or ACoA.

Conclusions: This profile of executive disorders implies that the assessment should include both cognitive tests and a validated inventory for behavioral dysexecutive syndrome. Initial assessment may be performed with a short cognitive battery, such as the harmonization standards protocol. However, administration of a full cognitive battery is required in selected patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147602PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732595PMC
July 2016

Lateral Temporal Lobe: An Early Imaging Marker of the Presymptomatic GRN Disease?

J Alzheimers Dis 2015 ;47(3):751-9

Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, ICM, Paris, France.

The preclinical stage of frontotemporal lobar degeneration (FTLD) is not well characterized. We conducted a brain metabolism (FDG-PET) and structural (cortical thickness) study to detect early changes in asymptomatic GRN mutation carriers (aGRN+) that were evaluated longitudinally over a 20-month period. At baseline, a left lateral temporal lobe hypometabolism was present in aGRN+ without any structural changes. Importantly, this is the first longitudinal study and, across time, the metabolism more rapidly decreased in aGRN+ in lateral temporal and frontal regions. The main structural change observed in the longitudinal study was a reduction of cortical thickness in the left lateral temporal lobe in carriers. A limit of this study is the relatively small sample (n = 16); nevertheless, it provides important results. First, it evidences that the pathological processes develop a long time before clinical onset, and that early neuroimaging changes might be detected approximately 20 years before the clinical onset of disease. Second, it suggests that metabolic changes are detectable before structural modifications and cognitive deficits. Third, both the baseline and longitudinal studies provide converging results implicating lateral temporal lobe as early involved in GRN disease. Finally, our study demonstrates that structural and metabolic changes could represent possible biomarkers to monitor the progression of disease in the presymptomatic stage toward clinical onset.
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http://dx.doi.org/10.3233/JAD-150270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923734PMC
July 2016

A phenotype of atypical apraxia of speech in a family carrying SQSTM1 mutation.

J Alzheimers Dis 2015 ;43(2):625-30

CHU Nantes, Centre de Mémoire et de Ressource et Recherche (CM2R), Nantes, France Inserm, CIC 04, Nantes, France.

SQSTM1 mutations, coding for the p62 protein, were identified as a monogenic cause of Paget disease of bone and of amyotrophic lateral sclerosis. More recently, SQSTM1 mutations were identified in few families with frontotemporal dementia. We report a new family carrying SQSTM1 mutation and presenting with a clinical phenotype of speech apraxia or atypical behavioral disorders, associated with early visuo-contructional deficits. This study further supports the implication of SQSTM1 in frontotemporal dementia, and enlarges the phenotypic spectrum associated with SQSTM1 mutations.
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http://dx.doi.org/10.3233/JAD-141512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337967PMC
July 2015

Frontotemporal dementia and its subtypes: a genome-wide association study.

Lancet Neurol 2014 Jul;13(7):686-99

University of Milan, Milan, Italy; Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.

Background: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.

Methods: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms.

Findings: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis.

Interpretation: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD.

Funding: The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.
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http://dx.doi.org/10.1016/S1474-4422(14)70065-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112126PMC
July 2014

[Frontal variant of frontotemporal dementia].

Geriatr Psychol Neuropsychiatr Vieil 2014 Mar;12(1):63-73

Centre mémoire ressources et recherche, Hôpital Laennec, CHU de Nantes, France ; Labo EMC, EA3082, Université Lyon 2, Bron, France.

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.
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http://dx.doi.org/10.1684/pnv.2014.0451DOI Listing
March 2014

DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes.

JAMA Neurol 2014 Feb;71(2):208-15

Université Pierre et Marie Curie Université Paris 06, Unité Mixte de Recherche (UMR)_S975, Paris, France2Institut National de la Santé et de la Récherche Médicale, UMR_S975, Centre de Recherche Institut du Cerveau et de la Moelle, Paris, France3Centre Nat.

Importance: Progressive supranuclear palsy (PSP) is usually sporadic, but few pedigrees with familial clustering of PSP-like phenotypes have been described. Occasionally, MAPT, C9ORF72, and TARDBP mutations have been identified.

Objective: To analyze the DCTN1 gene in 19 families with a clinical phenotype of PSP (PSP-like phenotype).

Design, Setting, And Participants: Sequencing of the DCTN1 gene in familial forms of PSP at a referral center among 21 patients with familial PSP-like phenotypes. In addition, 8 patients and relatives from a family carrying a DCTN1 mutation were evaluated.

Main Outcomes And Measures: Identification of the DCTN1 mutation and clinical description of DCTN1 mutation carriers.

Results: We identified a DCTN1 mutation in a large family characterized by high intrafamilial clinical phenotype variability. Two patients had PSP-like phenotypes with dystonia, vertical gaze slowness, dysexecutive syndrome, predominant axial rigidity, and midbrain atrophy on brain magnetic resonance imaging. The other patients manifested Perry syndrome, isolated parkinsonism, or a predominant behavioral variant of frontotemporal dementia.

Conclusions And Relevance: Mutations of the DCTN1 gene have been previously associated with amyotrophic lateral sclerosis and with Perry syndrome, a rare autosomal dominant disorder characterized by weight loss, parkinsonism, central hypoventilation, and psychiatric disturbances. Our study demonstrates that DCTN1 mutations should be searched for in patients with clinical PSP-like phenotypes and a behavioral variant of frontotemporal dementia, especially when a familial history of dementia, psychiatric disturbances, associated parkinsonism, or an autosomal dominant disorder is present.
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http://dx.doi.org/10.1001/jamaneurol.2013.5100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169198PMC
February 2014

C9ORF72 repeat expansions in the frontotemporal dementias spectrum of diseases: a flow-chart for genetic testing.

J Alzheimers Dis 2013 ;34(2):485-99

CRicm-UMRS975, Paris, France AP-HP, Hôpital de la Pitié-Salpêtrière, Centre de Référence des Démences Rares, Paris, France.

Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.
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http://dx.doi.org/10.3233/JAD-121456DOI Listing
October 2013

Prospective evaluation of behavioral scales in the behavioral variant of frontotemporal dementia.

Dement Geriatr Cogn Disord 2012 23;34(2):75-82. Epub 2012 Aug 23.

Centre Mémoire Recherche et Ressources (CMRR), Nantes, France.

Background: The Neuropsychiatric Inventory (NPI) and the Frontal Behavioral Inventory (FBI) are widely used in patients with the behavioral variant of frontotemporal dementia (bvFTD). Yet, few data are available on the long-term relevance of these scales.

Material And Methods: Based on a bvFTD population that participated in the Memantine Clinical Trial (NCT00200538), we studied the evolution and correlation between scores obtained on behavioral scales (NPI and FBI), cognitive scales [Mini-Mental State Examination (MMSE) and Mattis Dementia Rating Scale (MDRS)] and a burden scale [Zarit Burden Inventory (ZBI)]. The assessments were performed at 1 year in 41 patients and at 2 years in 23 patients who agreed to participate in this open-label study.

Results: The 2-year scores obtained on the FBI were significantly higher than the scores at inclusion while those obtained on the NPI did not change. There were significant correlations between the FBI, and the MDRS and MMSE, especially regarding the negative items. The ZBI correlated with behavioral scales at all stages for positive items.

Conclusions: This study based on a large population shows that the FBI is a better tool than the NPI for the long-term assessment of bvFTD patients. Moreover, the FBI allows a distinction to be made between behavioral disturbances that involve cognitive functions from those which have an important impact on caregiver burden.
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http://dx.doi.org/10.1159/000341784DOI Listing
February 2013

Validation of AclarusDx™, a blood-based transcriptomic signature for the diagnosis of Alzheimer's disease.

J Alzheimers Dis 2012 ;32(1):169-81

Exonhit SA, Paris, France.

Biomarkers have gained an increased importance in the past years in helping physicians to diagnose Alzheimer's disease (AD). This study was designed to identify a blood-based, transcriptomic signature that can differentiate AD patients from control subjects. The performance of the signature was then evaluated for robustness in an independent blinded sample population. RNA was extracted from 177 blood samples (90 AD patients and 87 controls) and gene expression profiles were generated using the human Genome-Wide Splice Array™. These profiles were used to establish a signature to differentiate AD patients from controls. Subsequently, prediction results were optimized by establishing grey zone boundaries that discount prediction scores near the disease status threshold. Signature validation was then performed on a blinded independent cohort of 209 individuals (111 AD and 98 controls). The AclarusDx™ signature consists of 170 probesets which map to 136 annotated genes, a significant number of which are associated with inflammatory, gene expression, and cell death pathways. Additional signature genes are known to interact with pathways involved in amyloid and tau metabolism. The validation sample set, after removal of 45 individuals with prediction profile scores within the grey zone, consisted of 164 subjects. The AclarusDx™ performance on this validation cohort had a sensitivity of 81.3% (95% CI: [73.3%; 89.3%]); and a specificity of 67.1% (95% CI: [56.3%; 77.9%]). AclarusDx™ is a non-invasive blood-based transcriptomic test that, in combination with standard assessments, can provide physicians with objective information to support the diagnosis of AD.
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http://dx.doi.org/10.3233/JAD-2012-120637DOI Listing
February 2013

A genome-wide study reveals rare CNVs exclusive to extreme phenotypes of Alzheimer disease.

Eur J Hum Genet 2012 Jun 14;20(6):613-7. Epub 2011 Dec 14.

Inserm U614, Faculté de Médecine, Rouen, France.

Studying rare extreme forms of Alzheimer disease (AD) may prove to be a useful strategy in identifying new genes involved in monogenic determinism of AD. Amyloid precursor protein (APP), PSEN1, and PSEN2 mutations account for only 85% of autosomal dominant early-onset AD (ADEOAD) families. We hypothesised that rare copy number variants (CNVs) could be involved in ADEOAD families without mutations in known genes, as well as in rare sporadic young-onset AD cases. Using high-resolution array comparative genomic hybridisation, we assessed the presence of rare CNVs in 21 unrelated ADEOAD cases, having no alteration on known genes, and 12 sporadic AD cases, with an age of onset younger than 55 years. The analysis revealed the presence of 7 singleton CNVs (4 in ADEOAD and 3 in sporadic cases) absent in 1078 controls and 912 late-onset AD cases. Strikingly, 4 out of 7 rearrangements target genes (KLK6, SLC30A3, MEOX2, and FPR2) encoding proteins that are tightly related to amyloid-β peptide metabolism or signalling. Although these variants are individually rare and restricted to particular subgroups of patients, these findings support the causal role, in human pathology, of a set of genes coding for molecules suspected for a long time to modify Aβ metabolism or signalling, and for which animal or cellular models have already been developed.
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http://dx.doi.org/10.1038/ejhg.2011.225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355247PMC
June 2012

Value of neuropsychological testing, imaging, and CSF biomarkers for the differential diagnosis and prognosis of clinically ambiguous dementia.

J Alzheimers Dis 2012 ;28(2):323-36

CHU Nantes, Centre de Mémoire et de Ressource et Recherche (CM2R), Nantes, France.

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-β 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.
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http://dx.doi.org/10.3233/JAD-2011-110761DOI Listing
May 2012

Memantine in behavioral variant frontotemporal dementia: negative results.

J Alzheimers Dis 2011 ;23(4):749-59

CMRR, Centre d'Investigation Clinique, Clinique Neurologique, Hôpital R et G Laënnec, Boulevard Jacques Monod, Nantes, France.

We tested the efficacy and tolerability of one-year treatment with memantine (10 mg bid) in behavioral variant frontotemporal dementia (bvFTD). BvFTD patients aged 45 to 75 years, with a Mini-Mental Status Examination (MMSE) score ≥19, were enrolled in a national, randomized, double-blind, placebo-controlled (DBPC), Phase II trial. The primary endpoint was the CIBIC-Plus (Clinician's Interview-Based Impression of Change Plus Caregiver Input). The secondary endpoints included: Neuropsychiatric Inventory (NPI), Frontal Behavioral Inventory (FBI), Mattis Dementia Rating Scale (MDRS), MMSE, Disability Assessment for Dementia (DAD), and the Zarit Burden Inventory (ZBI). Forty-nine patients were analyzed. At baseline, mean age was 65.6 years and mean MMSE was 25.0 (range: 19-30). On the CIBIC-Plus, 52 weeks after baseline, there were no significant differences between the memantine group (n = 23) and the placebo group (n = 26); p = 0.4458; however, 10 patients had worsened in the memantine group versus 17 in the placebo group. For the secondary endpoints there were no differences in the evolution of score between the memantine group and the placebo group (MMSE, p = 0.63); (MDRS, p = 0.95); (NPI, p = 0.25); (ZBI, p = 0.43); (DAD, p = 0.10) except for the FBI score, which was lower in the memantine group (p = 0.0417). Memantine was well-tolerated. This is the first DBPC trial in a large group of bvFTD patients involving neuroprotective treatment. A multinational study with a larger number of patients is now needed in order to verify the results of our study. The trial is registered with ClinicalTrials.gov; number NCT 00200538.
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http://dx.doi.org/10.3233/JAD-2010-101632DOI Listing
March 2012

[Caregiver burden in dementia: relationships with the activities of daily living, behavioral, and psychological symptoms].

Psychol Neuropsychiatr Vieil 2009 Dec;7 Spec No 1:15-20

Centre de la mémoire, Clinique neurologique, CHU de Nantes.

The prevalence of Alzheimer disease and other dementia is increasing. Caregivers' burden is a major determinant of patient's institutionalization. Therefore, it seems relevant to take it into account to postpone nursing home placement. Zarit Burden Inventory (ZBI) is the most widely used tool to assess the caregiver burden. Recent studies have shown that it is not correlated to the patients' daily functional abilities, but to the patient's level of behavioral disturbances. It also depends on how they are experienced by the caregiver and, in particular, on the caregiver's personality. This encourages the development of caregiver group interventions aimed to improve their coping strategies.
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http://dx.doi.org/10.1684/pnv.2009.0192DOI Listing
December 2009

Frontal Assessment Battery is a marker of dorsolateral and medial frontal functions: A SPECT study in frontotemporal dementia.

J Neurol Sci 2008 Oct;273(1-2):84-7

Service Central de Biophysique et Médecine Nucléaire, Hôpital de la Timone, APHM, Marseille, France.

The objective of this study is to identify the cerebral regions that are assessed by the Frontal Assessment Battery (FAB). Using SPM voxel-based analysis, we looked for correlations between FAB performance and brain SPECT perfusion in 47 patients with the frontal variant of frontotemporal dementia (fv-FTD) recruited by the French FTD research network, a multicentre initiative of French University hospitals with expertise in the field of dementia. A significant correlation was found between FAB performance and perfusion in the medial and dorsolateral frontal cortex bilaterally, independently of age, gender and MMSE. No correlations were observed with orbital frontal or parietal perfusion, in spite of the presence of hypoperfusion in these areas, or with perfusion of any other cortical or subcortical region. These findings confirm that the FAB is an adequate tool for assessing functions related to the dorsolateral and medial frontal cortex, and is thus useful for the evaluation of diseases associated with frontal dysfunction.
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http://dx.doi.org/10.1016/j.jns.2008.06.035DOI Listing
October 2008

Zarit burden inventory and activities of daily living in the behavioral variant of frontotemporal dementia.

Dement Geriatr Cogn Disord 2008 19;25(3):272-7. Epub 2008 Feb 19.

Memory Clinic, Department of Neurology, University Hospital, Nantes, France.

Background: Activities of daily living (ADL) and caregiver burden are known to have a major impact on the decision to institutionalize patients with Alzheimer's disease (AD), yet little research has been done on these aspects in patients with frontotemporal dementia (FTD).

Aim: To compare ADL and caregiver burden in FTD and in early-onset AD.

Methods: We compared 26 FTD and 28 AD patients with respect to the Neuropsychiatric Inventory (NPI), Mini Mental State Examination, Mattis Dementia Rating Scale (MDRS), Disability Assessment for Dementia (DAD) and Zarit Burden Inventory (ZBI).

Results: Demographic variables for FTD and AD were similar. FTD patients obtained a significantly higher NPI behavioral score than AD patients (median, 39.5 vs. 11; p < 0.0001). However, the two groups did not differ in their total DAD score. No correlations were observed between DAD and cognitive status (MDRS) or between DAD and behavioral impairment (NPI). The ZBI was higher in FTD than in AD patients (median, 40 vs. 18.5; p = 0.0004) and was correlated with the NPI in both groups.

Conclusion: Functional disability was similar in FTD and AD patients. Nevertheless, the caregiver burden was higher in FTD than in AD, a result that has important implications for caregiver help.
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http://dx.doi.org/10.1159/000117394DOI Listing
May 2008

Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study.

Brain 2008 Mar 1;131(Pt 3):732-46. Epub 2008 Feb 1.

1INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, F-75013, Paris, France.

Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.
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http://dx.doi.org/10.1093/brain/awn012DOI Listing
March 2008

[Semantic dementia].

Psychol Neuropsychiatr Vieil 2007 Jun;5(2):127-38

Centre mémoire de ressource et de recherche, Service de neurologie, CHU Pontchaillou. Rennes.

Semantic dementia (SD) is characterized by an assymetric atrophy of the temporal lobes and, clinically, by an impairment of the semantic memory associated to psychobehavioral symptoms. The concept of SD was defined in 1989 and still remains controversial. Some authors consider DS as a specific entity, others as part of the frontotemporal dementia (FTD) or a variant of the progressive aphasia syndrome. Many arguments tend to include SD in the FTD. However, SD presents a high interest for the comprehension of the organization of semantic memory in man, and is often associated with specific histopathologic lesions (ubiquitine positive and tau negative). Therefore SD should be considered as a clinical specific entity.
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June 2007

Progranulin null mutations in both sporadic and familial frontotemporal dementia.

Hum Mutat 2007 Sep;28(9):846-55

INSERM, UMR679, Paris, France.

Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD.
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http://dx.doi.org/10.1002/humu.20520DOI Listing
September 2007

Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia.

Hum Mutat 2007 Apr;28(4):416

Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.

Null mutations in the progranulin gene (GRN, PGRN) were recently identified as the causal mechanism underlying frontotemporal dementia (FTD) with ubiquitin-positive brain pathology linked to chromosome 17 (FTDU-17). In a Belgian and French FTD series comprising 332 patients, we reported 13 PGRN null mutations which were mainly nonsense and frameshift mutations resulting in premature stop codons. Here we report in the same patient series three missense mutations of which two (c.743C>T, p.Pro248Leu and c.1294C>T, p.Arg432Cys) were predicted in silico to severely affect protein folding and/or processing leading to PGRN protein haploinsufficiency. In addition, we observed three sequence variations in the 5' regulatory region that might potentially affect PGRN transcription activity. Our findings extend the mutation spectrum in PGRN leading to loss of functional PGRN as the basis for FTD.
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http://dx.doi.org/10.1002/humu.9484DOI Listing
April 2007

Demographic, neurological and behavioural characteristics and brain perfusion SPECT in frontal variant of frontotemporal dementia.

Brain 2006 Nov;129(Pt 11):3051-65

AP-HP, Hôpital de la Salpêtrière, Centre de Neuropsychologie UPMC, Paris, France.

We conducted a French multicentric cross-sectional study to describe in detail the demographic, neurological and behavioural characteristics of the frontal variant of frontotemporal dementia (fvFTD) and to characterize the pattern of brain perfusion SPECT in comparison to a healthy control group. A total of 68 fvFTD patients had technetium-99m-ECD brain perfusion SPECT at inclusion, 61 of which also underwent an in-depth evaluation including 70 items assessing behaviour, language and affect/emotion at onset and at inclusion. The mean age-at-onset was 60.4 +/- 7.8 years (35-75). Twenty-six per cent of the patients were older than 65 at onset. A positive familial history consistent with an autosomal dominant inheritance was found in 18% of the patients. At onset, the behavioural profile was predominantly inert in 25% of the patients, disinhibited in 18% and mixed in others. The behavioural features progressed to predominantly mixed or inert forms. Although, inertia was associated with predominant medial frontal and cingulate hypoperfusion, and patients with disinhibition exhibited predominant ventromedial prefrontal and temporal hypoperfusion, there were no major clinical differences between disinhibited and inert patients. Forty-five per cent of the deceased patients survived <6 years (short survival), and 34% of the patients survived >8 years (long survival). This shows that the final outcome of fvFTD is highly variable. No clinical factors predictive of short or long survival were identified. Unexpected, however, was the finding that brainstem hypoperfusion distinguished patients with a short survival from patients with long survival. In conclusion, this study shows that fvFTD is clinically a rather homogeneous entity. It also provides evidence that different behavioural presentations at onset are related to different anatomical localizations of degenerative damage. Finally, it demonstrates the prognostic value of brainstem hypoperfusion in a subgroup of patients with a short survival.
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http://dx.doi.org/10.1093/brain/awl288DOI Listing
November 2006

Phenotype associated with APP duplication in five families.

Brain 2006 Nov 7;129(Pt 11):2966-76. Epub 2006 Sep 7.

Department of Neurology, University Hospital IFRMP, France.

Different duplications of the APP locus have been identified in five families with autosomal dominant early onset Alzheimer's disease (ADEOAD) and Abeta-related cerebral amyloid angiopathy (CAA). This study describes the phenotype of this new entity. Clinical, neuropsychological, imagery and neuropathological data were reviewed. The phenotype was not dependent on the size of the duplication and there was no clinical feature of Down's syndrome. Dementia was observed in all cases; intracerebral haemorrhage (ICH) was reported in 6 (26%) and seizures occurred in 12 (57%) of 21 patients. Age of onset of dementia ranged from 42 to 59 years, ICH from 53 to 64 years and age at death from 46 to 75 years. The neuropathological findings in five cases demonstrated Alzheimer's disease and severe CAA lesions that were reminiscent from those reported in brains of Down's syndrome patients. A striking feature consisted in intraneuronal Abetax-40 accumulation located in the granular cell layer of the dentate gyrus and in the pyramidal cell layer of the Ammon's horn.
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http://dx.doi.org/10.1093/brain/awl237DOI Listing
November 2006

APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy.

Nat Genet 2006 Jan 20;38(1):24-6. Epub 2005 Dec 20.

Inserm U614-IFRMP, Faculty of Medicine, Rouen, France.

We report duplication of the APP locus on chromosome 21 in five families with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral amyloid angiopathy (CAA). Among these families, the duplicated segments had a minimal size ranging from 0.58 to 6.37 Mb. Brains from individuals with APP duplication showed abundant parenchymal and vascular deposits of amyloid-beta peptides. Duplication of the APP locus, resulting in accumulation of amyloid-beta peptides, causes ADEOAD with CAA.
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http://dx.doi.org/10.1038/ng1718DOI Listing
January 2006

Neuroprotection and neurodegenerative diseases: from biology to clinical practice.

Alzheimer Dis Assoc Disord 2005 Oct-Dec;19(4):226-39

INSERM U488, Le Kremlin-Bicêtre, France.

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.
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http://dx.doi.org/10.1097/01.wad.0000189053.25817.d6DOI Listing
March 2006
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