Publications by authors named "François Sellal"

57 Publications

SOFIA catheter for direct aspiration of large vessel occlusion stroke: A single-center cohort and meta-analysis.

Interv Neuroradiol 2021 Apr 4:15910199211005328. Epub 2021 Apr 4.

Department of Neuroradiology, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Background And Purpose: Direct aspiration (DA) using large-bore distal aspiration catheters is an established strategy for the endovascular thrombectomy (EVT) of large-vessel occlusion stroke (LVOS). However, the performance of individual catheters like SOFIA has yet to be examined.

Methods: We present a cohort of 144 consecutive patients treated with first-line DA and SOFIA 6 F Plus catheter for LVOS. We also conducted a systematic review of the literature searching multiple databases for reports on thrombectomy with DA and SOFIA catheters and performed a meta-analysis of recanalization, safety, and clinical outcomes.

Results: In the study cohort a successful recanalization (mTICI 2b-3) rate of 75.7% was achieved with DA alone, the global rate for functional independence (90-day mRS 0-2) was 40.3%. For the metanalysis we selected nine articles that included a total of 758 patients treated with first-line thrombectomy with the SOFIA catheters. The mTICI 2b-3 rate was 71.6% (95%CI, 66.3-76.5%) while a rescue stent-retriever was used in 24.1% (95%CI, 17.7-31.9%) of cases. The overall mTICI2b-3 rate after DA and rescue therapy was 88.9% (95%CI, 82.6-93.1%). We found a pooled estimate of 45.6% (95%CI, 38.6-52.8%) for functional independence, a mortality within 90 days of 19% (95%CI, 14.1-25.0%) and a rate of 5.8% (95%CI, 4.2-8.0%) of symptomatic intracranial hemorrhage.

Conclusion: The DA approach for LVOS with the SOFIA catheters is highly effective with an efficacy and safety profile comparable to those found in contemporary thrombectomy trials and observational studies that use other devices or approaches.
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http://dx.doi.org/10.1177/15910199211005328DOI Listing
April 2021

CSF interleukin 6 is a useful marker to distinguish pseudotumoral CNS inflammatory diseases from primary CNS lymphoma.

J Neurol 2021 Feb 20. Epub 2021 Feb 20.

Service de Neurologie, Hôpitaux Civils de Colmar, Colmar, France.

Background: Interleukin 6 (IL-6) is a pleomorphic cytokine that can be found in the cerebrospinal fluid (CSF) in a wide spectrum of inflammatory pathologies of the central nervous system (CNS).

Objective: Our aim was to characterize the diagnostic significance of CSF IL-6 among various CNS inflammatory diseases with pseudotumoral lesions (CNSID) and primary CNS lymphoma (PCNSL).

Methods: We retrospectively analyzed the CSF IL-6 concentrations in 43 consecutive patients with suspected PCNSL. A total of 28 patients were positively diagnosed with PCNSL and 15 with CNSID. We verified the results with CSF IL-10, an established biomarker for PCNSL.

Results: In the PCNSL group, the median CSF IL-6 concentration was 8 pg/ml, interquartile range (IQR) 5-18.5. For the patients with CNSID, the median concentration was 70 pg/ml, IQR 5-1368. A group comparison showed significantly higher CSF IL-6 levels in patients with CNSID than in those with PCNSL (p = 0.032). Moreover, IL-6 was correlated with CSF cell count in the CNSID group (r = 0.56, p = 0.028), but not in the PCNSL group (r = 0.3, p = 0.13). We found significantly higher CSF IL-10 levels in patients with PCNSL than in patients with CNS inflammatory lesions (p < 0.001).

Discussion And Conclusions: Our study suggests that CSF IL-6 levels could represent, in addition to CSF IL-10, a useful biomarker in the differential diagnosis of CNSID and suspected PCNSL.
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http://dx.doi.org/10.1007/s00415-021-10453-5DOI Listing
February 2021

Facet Arthrodesis with the FFX Device: One-Year Results from a Prospective Multicenter Study.

Int J Spine Surg 2020 Dec 29;14(6):996-1002. Epub 2020 Dec 29.

Hôpitaux Civils de Colmar, Colmar, France.

Background: Facet osteosynthesis can be performed to treat facet syndrome (FS) and reduce spinal instability following laminectomy in patients with lumbar spinal stenosis (LSS). The present study evaluated clinical and radiological outcomes following facet osteosynthesis with the FFX device.

Methods: Patients with FS or LSS were prospectively enrolled in a single-arm, multicenter study. The device was placed at affected levels with or without concomitant posterior lumbar interbody fusion (PLIF) procedures. The visual analog scale (VAS) for back and leg pain and Oswestry Disability Index (ODI) were evaluated preoperatively and postoperatively. Computed tomography scans to assess fusion and migration were performed 1 year following surgery.

Results: Fifty-three patients (26 men/27 women) with a mean age of 65.0 ± 9.6 years (range: 37-83 years) were enrolled. A total of 205 FFX devices were implanted with 15 patients undergoing concurrent PLIF procedures. There were no intraoperative or postoperative surgical complication reported, and no patient required revision surgery. Mean VAS leg and back pain scores significantly improved from 5.57 to 2.09 ( < .001) and 5.74 to 3.13 ( < .001), respectively, between the preoperative and 1 year follow-up assessments. Mean ODI scores also significantly improved from 44.7% to 24.0% ( < .001) during the same time period. Facet fusion occurred with 86.3% of device placements after 12 months. There was 1 (0.5%) asymptomatic device migration. Eight devices (3.9%) were considered misplaced.

Conclusions: The use of the FFX device is associated with a significant reduction in both pain and disability following surgery with a high facet joint fusion rate.

Level Of Evidence: 4.

Clinical Relevance: This is the first study reporting clinical experience using the FFX device to facilitate facet osteosynthesis. The ability of the device to relieve pain, reduce disability, and enhance lumbar facet fusion with a low rate of device misplacement and migration was demonstrated.
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http://dx.doi.org/10.14444/7149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872413PMC
December 2020

The Babinski sign in Renaissance paintings-a reappraisal of the toe phenomenon in representations of the Christ Child: observational analysis.

BMJ 2020 12 10;371:m4556. Epub 2020 Dec 10.

Department of Anatomy and Department of Neuromuscular Diseases, CHRU Besançon, University of Franche-Comté, Besançon, France.

Objective: To investigate systematically the presence of the Babinski sign in paintings of the Christ Child by the greatest painters of the Renaissance.

Design: Observational analysis.

Setting: Large collection of paintings depicting the Christ Child from Flemish, Rhenish, and Italian schools between 1400 and 1550 CE, searched using published catalogues and Google.

Study Sample: 302 Renaissance paintings (by 19 painters) depicting the Christ Child.

Main Outcome Measure: Babinski sign, defined as a hallux extension with an amplitude greater than 30°. The presence of foot sole stimulation was also noted.

Results: An unquestionable upgoing toe was apparent in 90 (30%) of the 302 paintings. The Babinski sign was present in more than 60% of Christ Child paintings by Rogier van der Weyden, Hans Memling, Martin Schongauer, and Matthias Grünewald. A bilateral Babinski sign was observed in three paintings. Stimulation of the sole was noted in 48/90 (53%) paintings and was always present in paintings by Andrea del Verrocchio, Leonardo da Vinci, and Giorgione. No association existed between the presence of the Babinski sign and the period during which the painter was active.

Conclusions: Four main factors were noted in relation to the representation of the Babinski sign in paintings of the Christ Child: the physiological toe phenomenon in infants, the representation of the nudity of the Christ by painters during the 15th century to demonstrate the incarnation, Renaissance painters' need for precise observation of anatomy, and the desire of some Rhenish and Flemish painters to depict very realistic details. Italian Renaissance painters, whether Mannerist or not, tended to idealise the beauty of human body, and they often did not reproduce the Babinski sign.
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http://dx.doi.org/10.1136/bmj.m4556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726706PMC
December 2020

Semantic loss marks early Alzheimer's disease-related neurodegeneration in older adults without dementia.

Alzheimers Dement (Amst) 2020 5;12(1):e12066. Epub 2020 Aug 5.

Centre Inserm U1219 d'Epidémiologie et de Développement (ISPED) Bordeaux School of Public Health Institut de Santé Publique Université de Bordeaux Bordeaux France.

Objective: To assess progression of semantic loss in early stages of cognitive decline using semantic and letter fluency performance, and its relation with Alzheimer's disease (AD)-specific neurodegeneration using longitudinal multimodal neuroimaging measures.

Methods: Change in verbal fluency was analyzed among 2261 non-demented individuals with a follow-up diagnosis of no mild cognitive impairment (MCI), amnestic MCI (aMCI), non-amnestic MCI (naMCI), or incident dementia, using linear mixed models across 4 years of follow-up, and relations with magnetic resonance imaging (MRI; n = 1536) and F-fluorodeoxyglucose brain positron emission tomography (F-FDG-PET) imaging (n = 756) using linear regression models across 2 years of follow-up.

Results: Semantic fluency declined-fastest in those at higher risk for AD (apolipoprotein E [APOE] e4 carriers, Clinical Dementia Rating score of .5, aMCI, or incident dementia)-while letter fluency did not except for those with incident dementia. Lower baseline semantic fluency was associated with an increase in white matter hyperintensities and total mean cortical thinning over time, and regionally with less hippocampal volume as well as more cortical thinning and reduced F-FDG-PET uptake in the inferior parietal lobule, entorhinal cortex, isthmus cingulate, and precuneus-posterior cingulate area. In contrast, baseline letter fluency was not associated with change in total nor regional neurodegeneration. Whole-brain neurodegeneration over time was associated with faster decline in both fluencies, while AD-specific regions were associated with a faster rate of decline in semantic but not letter fluency.

Interpretation: This study provides strong evidence of distinctive degeneration of semantic abilities early on in relation to both cognitive decline and AD-specific neurodegeneration.
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http://dx.doi.org/10.1002/dad2.12066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403823PMC
August 2020

Long-term effect of natalizumab in patients with RRMS: TYSTEN cohort.

Mult Scler 2021 Apr 9;27(5):729-741. Epub 2020 Jul 9.

Department of Neurology, Centre Hospitalier Universitaire de Lille, Lille, France/Department of Neuroradiology, Centre Hospitalier Universitaire de Lille, Lille, France.

Background: Data are needed on long-term effect of natalizumab (NTZ) in relapsing-remitting multiple sclerosis (RRMS).

Objectives: To evaluate the time of onset of secondary progressive phase in patients with an RRMS treated with NTZ and to investigate predictive factors.

Methods: TYSTEN is an observational study. Patients starting NTZ between 2007 and 2012 were included and followed up until October 2018. Relapses, Expanded Disability Status Scale (EDSS) scores, and results of brain magnetic resonance imaging (MRI) were collected each year. Data were used to estimate the cumulative probability of several poor outcomes such as secondary progressive multiple sclerosis (SPMS) conversion, EDSS worsening, EDSS 4.0, and EDSS 6.0.

Results: 770 patients were included. The mean follow-up duration was 97 months and the mean time exposure to NTZ was 66 months. At 10 years, the cumulative probability of SPMS was 27.7%. Predictive factors for poor outcomes were a ⩾1-point increase in EDSS score from baseline, new T2 lesion or T1 gadolinium-enhancing lesion, the occurrence of relapse at 1 or 2 years and No Evidence of Disease Activity (NEDA-3; no relapse, no new T2 or T1 gadolinium-enhancing lesions, no progression) was a protective factor.

Conclusion: In our cohort of patients treated with NTZ, poor outcomes were infrequent and are driven by disease activity.
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http://dx.doi.org/10.1177/1352458520936239DOI Listing
April 2021

Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis.

JAMA Neurol 2020 09;77(9):1079-1088

Service de Neurologie, Clinical Investigation Center Institut National de la Santé et de la Recherche Médicale 1434, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France.

Importance: Risk factors associated with the severity of coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (MS) are unknown. Disease-modifying therapies (DMTs) may modify the risk of developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities.

Objective: To describe the clinical characteristics and outcomes in patients with MS and COVID-19 and identify factors associated with COVID-19 severity.

Design, Setting, And Participants: The Covisep registry is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. The study included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020.

Exposures: COVID-19 diagnosed with a polymerase chain reaction test on a nasopharyngeal swab, thoracic computed tomography, or typical symptoms.

Main Outcomes And Measures: The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1 [not hospitalized with no limitations on activities] to 7 [death]) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Scale score (EDSS; ranging from 0 to 10, with cutoffs at 3 and 6), comorbidities, COVID-19 characteristics, and outcomes. Univariate and multivariate logistic regression models were used to estimate the association of collected variables with COVID-19 outcomes.

Results: A total of 347 patients (mean [SD] age, 44.6 [12.8] years, 249 women; mean [SD] disease duration, 13.5 [10.0] years) were analyzed. Seventy-three patients (21.0%) had a COVID-19 severity score of 3 or more, and 12 patients (3.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 284 patients (81.8%) were receiving DMT. There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients with no DMT relative to patients receiving DMTs (46.0% vs 15.5%; P < .001). Multivariate logistic regression models determined that age (odds ratio per 10 years: 1.9 [95% CI, 1.4-2.5]), EDSS (OR for EDSS ≥6, 6.3 [95% CI. 2.8-14.4]), and obesity (OR, 3.0 [95% CI, 1.0-8.7]) were independent risk factors for a COVID-19 severity score of 3 or more (indicating hospitalization or higher severity). The EDSS was associated with the highest variability of COVID-19 severe outcome (R2, 0.2), followed by age (R2, 0.06) and obesity (R2, 0.01).

Conclusions And Relevance: In this registry-based cohort study of patients with MS, age, EDSS, and obesity were independent risk factors for severe COVID-19; there was no association found between DMTs exposure and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of patients with MS during the COVID-19 pandemic.
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http://dx.doi.org/10.1001/jamaneurol.2020.2581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320356PMC
September 2020

An Arabic Version of the Mini-Mental State Examination for the Lebanese Population: Reliability, Validity, and Normative Data.

J Alzheimers Dis 2019 08;71(2):525-540

Department of Neurology, Hôpitaux Civils de Colmar and INSERM U-1118, School of Medicine, Strasbourg University, France.

Background: The Mini-Mental State Examination (MMSE) has not been validated in the Lebanese population and no normative data exist at the national level.

Objective: To evaluate the reliability and validity of an Arabic version of MMSE developed by the "Groupe de Travail sur les Démences de l'Université Saint Joseph" (A-MMSE(GTD-USJ)) and to provide normative data by gender, age, and education in adults over 55.

Methods: Study design: national cross-sectional survey.

Study Population: 1,010 literate community-dwelling Lebanese residents aged 55 and above.

Outcomes: reproducibility, internal consistency, sensitivity, specificity, predictive values, and area under the curve of the A-MMSE(GTD-USJ) for the detection of cognitive impairment using the Clinical Dementia Rating (CDR) as the gold standard. Normative data were established from 720 healthy adults. A-MMSE(GTD-USJ) scores corresponding to the 5th, 10th, 15th, and 50th percentiles were identified according to gender, age, and education.

Results: Intra-rater and inter-rater test-retest score correlations were 0.89 and 0.72, respectively. Cronbach alpha coefficient for internal consistency of the A-MMSE(GTD-USJ) was 0.71. A threshold value of 23 provided a sensitivity of 80% and a specificity of 89.4%. The area under the curve was 0.92. A-MMSE(GTD-USJ) scores increased with education and decreased with age. Women had significantly lower scores than men. Normative data for A-MMSE(GTD-USJ) stratified by gender, age, and education were generated.

Conclusion: In reference to the CDR, the A-MMSE(GTD-USJ) is a valid tool to assess cognitive status among Lebanese subjects aged 55 and above. Normative data will help clinicians in detecting cognitive impairment in this population.
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http://dx.doi.org/10.3233/JAD-181232DOI Listing
August 2019

Bilateral fronto-insular FLAIR hyperintensities: discussion on a case of new-onset refractory status epilepticus.

Acta Neurol Belg 2019 Sep 19;119(3):467-469. Epub 2019 Apr 19.

Department of Neurology, Hôpitaux Civils, Colmar, France.

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http://dx.doi.org/10.1007/s13760-019-01141-3DOI Listing
September 2019

Long-lasting diagonistic dyspraxia suppressed by rTMS applied to the right motor cortex.

J Neurol 2019 Mar 10;266(3):631-635. Epub 2019 Jan 10.

Gerontology Pole, Hôpitaux Civils, Colmar, France.

We describe the case of a 58-year-old patient with complete callosal agenesis, who developed after a stroke a long lasting and distressing diagonistic dyspraxia. We found two original treatments to relieve the patient from his left limb conflicting movements. Reinforcing left arm sensory input minimized dyspraxic movements but was difficult to apply daily and was found unsatisfactory by the patient. As left anarchic, unwished movements of diagonistic dyspraxia have been attributed to the lack of inhibition exerted by supplementary motor area on right motor cortex, we applied sham-controlled rTMS to the right motor cortex. This procedure provided a dramatic suppression of left-hand involuntary movements. To our knowledge, this is the first description of the successful treatment of diagonistic dyspraxia.
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http://dx.doi.org/10.1007/s00415-018-09178-9DOI Listing
March 2019

France Will No More Reimburse Available Symptomatic Drugs Against Alzheimer's Disease.

J Alzheimers Dis 2018 ;66(2):425-427

Fédération des Centres Mémoire, Lyon, France.

The French Minister of Health published a decree on May 29th of 2018 removing the drugs used to fight against symptoms due to Alzheimer's disease (donepezil, rivastigmine, galantamine, memantine) from the list of available reimbursed drugs. This follows the advice delivered by the High Authority for Health in 2016 and 2018 stating an "insufficient medical benefit and dangerousness because of significant side effects". The main French scientific and medical societies and professional associations want to state here their deep disagreement regarding this unfair decision. The evidence-based medicine related to these drugs reaches a high level in literature, whereas the clinical relevance of these treatments must be considered with co-prescription of psychosocial interventions and related approaches. As no serious pharmacovigilance signal has been provided by health authorities, the ratio of benefits/risks favors these drugs.
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http://dx.doi.org/10.3233/JAD-180843DOI Listing
October 2019

Cognitive and imaging markers in non-demented subjects attending a memory clinic: study design and baseline findings of the MEMENTO cohort.

Alzheimers Res Ther 2017 Aug 29;9(1):67. Epub 2017 Aug 29.

Centre Inserm U1219, Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Bordeaux School of Public Health, Université de Bordeaux, 146 rue Léo Saignat, 33076, Bordeaux cedex, France.

Background: The natural history and disease mechanisms of Alzheimer's disease and related disorders (ADRD) are still poorly understood. Very few resources are available to scrutinise patients as early as needed and to use integrative approaches combining standardised, repeated clinical investigations and cutting-edge biomarker measurements.

Methods: In the nationwide French MEMENTO cohort study, participants were recruited in memory clinics and screened for either isolated subjective cognitive complaints (SCCs) or mild cognitive impairment (MCI; defined as test performance 1.5 SD below age, sex and education-level norms) while not demented (Clinical Dementia Rating [CDR] <1). Baseline data collection included neurological and physical examinations as well as extensive neuropsychological testing. To be included in the MEMENTO cohort, participants had to agree to undergo both brain magnetic resonance imaging (MRI) and blood sampling. Cerebral F-fluorodeoxyglucose positon emission tomography and lumbar puncture were optional. Automated analyses of cerebral MRI included assessments of volumes of whole-brain, hippocampal and white matter lesions.

Results: The 2323 participants, recruited from April 2011 to June 2014, were aged 71 years, on average (SD 8.7), and 62% were women. CDR was 0 in 40% of participants, and 30% carried at least one apolipoprotein E ε4 allele. We observed that more than half (52%) of participants had amnestic mild cognitive impairment (17% single-domain aMCI), 32% had non-amnestic mild cognitive impairment (16.9% single-domain naMCI) and 16% had isolated SCCs. Multivariable analyses of neuroimaging markers associations with cognitive categories showed that participants with aMCI had worse levels of imaging biomarkers than the others, whereas participants with naMCI had markers at intermediate levels between SCC and aMCI. The burden of white matter lesions tended to be larger in participants with aMCI. Independently of CDR, all neuroimaging and neuropsychological markers worsened with age, whereas differences were not consistent according to sex.

Conclusions: MEMENTO is a large cohort with extensive clinical, neuropsychological and neuroimaging data and represents a platform for studying the natural history of ADRD in a large group of participants with different subtypes of MCI (amnestic or not amnestic) or isolated SCCs.

Trial Registration: Clinicaltrials.gov, NCT01926249 . Registered on 16 August 2013.
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http://dx.doi.org/10.1186/s13195-017-0288-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576287PMC
August 2017

Long-term cognitive outcome of Alzheimer's disease and dementia with Lewy bodies: dual disease is worse.

Alzheimers Res Ther 2017 Jun 27;9(1):47. Epub 2017 Jun 27.

University of Strasbourg, Laboratory of Biostatistics and French National Centre for Scientific Research (CNRS), ICube Laboratory, Team Modèles, Images et Vision (MIV), Strasbourg, France.

Background: Longitudinal studies of dementia with Lewy bodies (DLB) are rare. Clinically, DLB is usually considered to worsen into Alzheimer's disease (AD). The aim of our study was to compare the rate of the cognitive decline in DLB, AD, and the association of the two diseases (AD + DLB).

Methods: Using the Regional Network for Diagnostic Aid and Management of Patients with Cognitive Impairment database, which includes all the patients seen at all memory clinics (medical consultation and day hospitals) in four French regions, and beta regression, we compared the longitudinal the Mini-Mental State Examination scores of 1159 patients with AD (n = 1000), DLB (n = 131) and AD + DLB (association of the two) (n = 28) during follow-up of at least 4 years.

Results: The mean follow-up of the patients was 5.88 years. Using beta regression without propensity scores, the comparison of the decline of patients with AD and patients with DLB did not show a significant difference, but the decline of patients with AD + DLB was worse than that of either patients with DLB (P = 0.006) or patients with AD (P < 0.001). Using beta regression weighted by a propensity score, comparison of patients with AD and patients with DLB showed a faster decline for patients with DLB (P < 0.001). The comparison of the decline of patients with AD + DLB with that of patients with DLB (P < 0.001) and patients with AD (P < 0.001) showed that the decline was clearly worse in the patients with dual disease.

Conclusions: Whatever the analysis, the rate of decline is faster in patients with AD + DLB dual disease. The identification of such patients is important to enable clinicians to optimise treatment and care and to better inform and help patients and caregivers.
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http://dx.doi.org/10.1186/s13195-017-0272-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488368PMC
June 2017

APP Mutations in Cerebral Amyloid Angiopathy with or without Cortical Calcifications: Report of Three Families and a Literature Review.

J Alzheimers Dis 2017 ;56(1):37-46

CNR-MAJ, Rouen University Hospital, Rouen, France.

Background: Specific APP mutations cause cerebral amyloid angiopathy (CAA) with or without Alzheimer's disease (AD).

Objective: We aimed at reporting APP mutations associated with CAA, describe the clinical, cerebrospinal fluid AD biomarkers, and neuroimaging features, and compare them with the data from the literature.

Methods: We performed a retrospective study in two French genetics laboratories by gathering all clinical and neuroimaging data from patients referred for a genetic diagnosis of CAA with an age of onset before 66 years and fulfilling the other Boston revised criteria. We studied the segregation of mutations in families and performed a comprehensive literature review of all cases reported with the same APP mutation.

Results: We screened APP in 61 unrelated French patients. Three mutations, located in the Aβ coding region, were detected in five patients from three families: p.Ala692Gly (Flemish), p.Glu693Lys (Italian), and p.Asp694Asn (Iowa). Patients exhibited CAA and progressive cognitive impairment associated with cortical calcifications in the Iowa and Italian mutation carriers, but not the patient carrying the Flemish mutation.

Conclusions: This is the first evidence of cortical calcification in patients with an APP mutation other than the Iowa mutation. We discuss the radiological, cerebrospinal fluid, and clinical phenotype of patients carrying these mutations in the literature.
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http://dx.doi.org/10.3233/JAD-160709DOI Listing
February 2018

Mystery Case: Metronidazole-induced encephalopathy.

Neurology 2016 08;87(9):e89-90

From the Department of Radiology (A.D.), Centre Hospitalier de Mulhouse; and the Departments of Neuroradiology (I.M.) and Neurology (M.-H.D., F.S.), Hôpitaux Civils, Colmar Cedex, France.

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http://dx.doi.org/10.1212/WNL.0000000000003030DOI Listing
August 2016

Seizures in dominantly inherited Alzheimer disease.

Neurology 2016 Aug 27;87(9):912-9. Epub 2016 Jul 27.

From the Departments of Neurology (A.Z., A.B., O.M., D.H., D.W.) and Genetics (G.N., D.H.), and CNR-MAJ (A.Z., G.N., S.R., O.M., D.C., D.H.), Rouen University Hospital; Inserm U1079 (C.C., A.R.-L., G.N., S.R., D.C., D.H., D.W.), Normandy Centre for Genomic Medicine and Personalized Medicine, Rouen University, IRIB, Normandy University, Rouen; Department of Neurology (J.P.), CMRR and INSERM U825, Purpan University Hospital, Toulouse; CNR-MAJ (I.L.B.), Pitié-Salpêtrière Paris and CRCICM, IM2A, UMR-S975 AP-HP, University Hospital Pitié-Salpêtrière, Paris; Université Lille (F.P., A.R.-S.), Inserm U1171, Memory Centre and CNR-MAJ, CHU, Lille; Department of Neuropsychology (M.F., B.C.), CMRR, University Hospital, Groupe Hospitalier Est, Bron; Department of Neurology (M.S.), AP-HP, University Hospital Saint-Anne, Paris; Department of Neurology (C.B.-B.), CMRR, Nantes University Hospital; Department of Neurology and Neuropsychology (M.C.), Aix-Marseille University, CMRR, Timone Hospital and INSERM UMR1106, Marseille; CMRR Montpellier (A.G.), Department of Neurology, University Hospital of Montpellier and INSERM U1163, Montpellier; Department of Neurology (L.C.), CMRR, Besançon University Hospital; CMRR (F.B.), Department of Geriatrics, University Hospital of Strasbourg and ICube Laboratory, CNRS, University of Strasbourg; and CMRR Paris Nord AP-HP (C.P.), Hopital Lariboisière, INSERM, U942, Université Paris Diderot, Sorbonne Paris Cité, UMRS 942, Paris, France.

Objective: To assess seizure frequency in a large French cohort of autosomal dominant early-onset Alzheimer disease (ADEOAD) and to determine possible correlations with causative mutations.

Methods: A national multicentric study was performed in patients with ADEOAD harboring a pathogenic mutation within PSEN1, PSEN2, APP, or a duplication of APP, and a minimal follow-up of 5 years. Clinical, EEG, and imaging data were systematically recorded.

Results: We included 132 patients from 77 families: 94 PSEN1 mutation carriers (MCs), 16 APP duplication carriers, 15 APP MCs, and 7 PSEN2 MCs. Seizure frequency was 47.7% after a mean follow-up of 8.4 years (range 5-25). After 5-year follow-up and using a Cox model analysis, the percentages of patients with seizures were respectively 19.1% (10.8%-26.7%) for PSEN1, 28.6% (0%-55.3%) for PSEN2, 31.2% (4.3%-50.6%) for APP duplications, and no patient for APP mutation. APP duplication carriers showed a significantly increased seizure risk compared to both APP MCs (hazard ratio [HR] = 5.55 [95% confidence interval 1.87-16.44]) and PSEN1 MCs (HR = 4.46 [2.11-9.44]). Among all PSEN1 mutations, those within the domains of protein hydrophilic I, transmembrane II (TM-II), TM-III, TM-IV, and TM-VII were associated with a significant increase in seizure frequency compared to other domains (HR = 4.53 [1.93-10.65], p = 0.0005).

Conclusions: Seizures are a common feature of ADEOAD. In this population, risk was significantly higher in the APP duplication group than in all other groups. Within PSEN1, 5 specific domains were associated with a higher seizure risk indicating specific correlations between causative mutation and seizures.
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http://dx.doi.org/10.1212/WNL.0000000000003048DOI Listing
August 2016

A transgenic mouse expressing CHMP2Bintron5 mutant in neurons develops histological and behavioural features of amyotrophic lateral sclerosis and frontotemporal dementia.

Hum Mol Genet 2016 08 21;25(15):3341-3360. Epub 2016 Jun 21.

INSERM, U1118, Mécanismes Centraux et Périphériques de la Neurodégénérescence, F-67000 Strasbourg, France

Mutations in the charged multivesicular body protein 2B (CHMP2B) are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and with a mixed ALS-FTD syndrome. To model this syndrome, we generated a transgenic mouse line expressing the human CHMP2B mutant in a neuron-specific manner. These mice developed a dose-dependent disease phenotype. A longitudinal study revealed progressive gait abnormalities, reduced muscle strength and decreased motor coordination. CHMP2B mice died due to generalized paralysis. When paralyzed, signs of denervation were present as attested by altered electromyographic profiles, by decreased number of fully innervated neuromuscular junctions, by reduction in size of motor endplates and by a decrease of sciatic nerve axons area. However, spinal motor neurons cell bodies were preserved until death. In addition to the motor dysfunctions, CHMP2B mice progressively developed FTD-relevant behavioural modifications such as disinhibition, stereotypies, decrease in social interactions, compulsivity and change in dietary preferences. Furthermore, neurons in the affected spinal cord and brain regions showed accumulation of p62-positive cytoplasmic inclusions associated or not with ubiquitin and CHMP2B As observed in FTD3 patients, these inclusions were negative for TDP-43 and FUS. Moreover, astrogliosis and microgliosis developed with age. Altogether, these data indicate that the neuronal expression of human CHMP2B in areas involved in motor and cognitive functions induces progressive motor alterations associated with dementia symptoms and with histopathological hallmarks reminiscent of both ALS and FTD.
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http://dx.doi.org/10.1093/hmg/ddw182DOI Listing
August 2016

Semantic and nonfluent aphasic variants, secondarily associated with amyotrophic lateral sclerosis, are predominant frontotemporal lobar degeneration phenotypes in TBK1 carriers.

Alzheimers Dement (Amst) 2015 Dec 30;1(4):481-6. Epub 2015 Oct 30.

Institut du Cerveau et de la Moelle épinière (ICM), CNRS UMR 7225, INSERM U 1127, Sorbonne Universités, Université Pierre et Marie, Univ Paris 06, UPMC-P6 UMR S 1127 - Hôpital Pitié-Salpêtrière, Paris, France; APHP, Département des Maladies du Système Nerveux, Hôpital de la Salpêtrière, Paris, France; Centre de Référence des Démences Rares, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.

Introduction: TBK1 mutations represent a rare novel genetic cause of amyotrophic lateral sclerosis (ALS) without or with dementia. The full spectrum of TBK1 phenotypes has not been completely defined so far.

Methods: We describe the clinical and neuroimaging characteristics of loss-of-function mutation carriers initially presenting with frontotemporal lobar degeneration (FTLD) phenotypes.

Results: Two carriers initially presented semantic variant of FTLD (svFTLD); two other developed nonfluent variant of FTLD (nfvFTLD) and corticobasal syndrome (CBS), associated with severe anterior temporal and opercular atrophy. All secondarily developed ALS.

Discussion: This study enlarges the phenotypic spectrum of TBK1 mutations, including svFTLD and nfvFTLD/CBS, not reported so far. Aphasic presentations seem to be more evocative of TBK1 genotype than behavioral variant of FTLD, and TBK1 should be analyzed in patients with isolated FTLD at onset, particularly in rare aphasic cases secondarily associated with ALS.
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http://dx.doi.org/10.1016/j.dadm.2015.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879495PMC
December 2015

Epileptic Prodromal Alzheimer's Disease, a Retrospective Study of 13 New Cases: Expanding the Spectrum of Alzheimer's Disease to an Epileptic Variant?

J Alzheimers Dis 2016 04;52(3):1125-33

Unité de Neuropsychologie, Service de Neurologie des Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Background: Aside from rare case reports, only one study, with 12 patients, has addressed the phenotypic presentation of epilepsy in clinically defined amnestic mild cognitive impairment (aMCI, presumed to correspond to the AD prodromal stage): the authors highlighted a pharmacosensitive non-convulsive partial epileptic syndrome most probably related to the temporal or temporo-frontal cortices.

Objective: The objective of this study was to verify the existence and the syndromic features of epileptic prodromal AD in a tertiary Memory Clinic.

Methods: We conducted a retrospective, single-center study of the electro-radio-clinical features of 13 cases of epileptic prodromal AD patients (3.1% of a cohort of MCI, n = 430 subjects), selected on both clinical criteria and CSF biomarkers.

Results: In our patients, a pharmacosensitive temporal lobe epilepsy syndrome, inaugurating prodromal AD, started at a mean age of 63 years (±12.8 years) and preceded MCI diagnosis by 4 to 7 years. At the stage of aMCI, median MMSE score was 26 and imaging showed mild hippocampal atrophy. After almost one year under treatment, cognitive complaints were not relieved but the MMSE score remained stable at 26 for 11 patients (2 patients were excluded from analysis because of the onset of aphasic or neurovisual symptoms altering MMSE scoring).

Conclusion: Our data, in conjunction with those of the 12 previously described subjects, suggest the existence of a currently unrecognized inaugural epilepsy syndrome of sporadic AD. Such a syndrome could be called the epileptic variant of AD because seizures are its sole feature for more than 2.5 years.
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http://dx.doi.org/10.3233/JAD-150096DOI Listing
April 2016

Differential processing of hierarchical visual stimuli in young and older healthy adults: An event-related potentials (ERP) study.

Neuropsychology 2016 07 11;30(5):600-11. Epub 2016 Feb 11.

Laboratoire de Neuroscience Cognitive et Adaptatives, UMR 7364, CNRS/ Université de Strasbourg.

Objective: In tasks involving hierarchical stimuli, young subjects typically show faster RTs and higher accuracy rates in discriminating target stimuli at the global level than at the local level. This pattern of performance is called the global precedence effect (GPE). As individuals age, this patterns shifts to a local precedence effect (LPE). The purpose of this study was to determine whether the decline in GPE in older adults may be due to impairment of grouping processes.

Method: The authors recorded event-related potentials (ERP) while young and elderly subjects performed a global/local task in response to hierarchical stimuli, and they focused on the P300 component as an index of grouping processes.

Results: Compared to young subjects, elderly individuals showed a lower rate of correct discrimination in global processing conditions, but a higher rate of correct responses in local processing conditions, confirming a shift from a GPE to a LPE during aging. Interestingly, the P300 amplitude increased selectively during global processing in young adults but was not modulated by processing level in older participants. By contrast, the modulation of the early component N2 as a function of precedence level remained preserved in older subjects.

Conclusion: The results suggest that the precedence level may depend on early processes that are unaffected during aging. This may explain the preservation of local precedence effect in elderly individuals. However, global processing may depend on extra attentional processing occurring at later stages. The alteration of later processing may explain the decline in global precedence during aging. (PsycINFO Database Record
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http://dx.doi.org/10.1037/neu0000268DOI Listing
July 2016

Evaluating Behavior in Mouse Models of the Behavioral Variant of Frontotemporal Dementia: Which Test for Which Symptom?

Neurodegener Dis 2016 31;16(3-4):127-39. Epub 2015 Oct 31.

INSERM, U1118, Laboratoire des Mx00E9;canismes Centraux et Px00E9;riphx00E9;riques de la Neurodx00E9;gx00E9;nx00E9;rescence, Strasbourg, France.

The behavioral variant of frontotemporal dementia (bvFTD) is a neurodegenerative disease affecting people in their early sixties, characterized by dramatic changes in individual and social behavior. Despite the heterogeneity in the presentation of the clinical symptoms of bvFTD, some characteristic changes can be highlighted. Social disinhibition, changes in food preferences as well as loss of empathy and apathy are commonly described. This is accompanied by a characteristic and dramatic atrophy of the prefrontal cortex with the accumulation of protein aggregates in the neurons in this area. Several causative mutations in different genes have been discovered, allowing the development of transgenic animal models, especially mouse models. In mice, attention has been focused on the histopathological aspects of the pathology, but now studies are taking interest in assessing the behavioral phenotype of FTD models. Finding the right test corresponding to human symptoms is quite challenging, especially since the frontal cortex is much less developed in mice than in humans. Although challenging, the ability to detect relevant prefrontal cortex impairments in mice is crucial for therapeutic approaches. In this review, we aim to present the approaches that have been used to model the behavioral symptoms of FTD and to explore other relevant approaches to assess behavior involving the prefrontal cortex, as well as the deficits associated with FTD.
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http://dx.doi.org/10.1159/000439253DOI Listing
December 2016

TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts.

Neurobiol Aging 2015 Nov 14;36(11):3116.e5-3116.e8. Epub 2015 Aug 14.

Institut du Cerveau et de la Moelle épinière (ICM), INSERM U1127, CNRS UMR 7225, Sorbonne Universités, Université Pierre et Marie Curie, Univ Paris 06, UPMC-P6 UMR S 1127 Hôpital de la Pitié-Salpêtrière, Paris, France; Département des Maladies du Système Nerveux, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France; Département de Génétique et Cytogénétique, Unité Fonctionnelle de Génétique Clinique, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.08.009DOI Listing
November 2015

Effects of Low Amyloid-β (Aβ) Concentration on Aβ1-42 Oligomers Binding and GluN2B Membrane Expression.

J Alzheimers Dis 2015 ;47(2):453-66

Institut des Neurosciences Cellulaires et Intégratives-CNRS, Strasbourg, France.

Numerous studies have shown that amyloid-β (Aβ) modulate intracellular metabolic cascades and an intracellular Ca2+ homeostasis and a cell surface NMDA receptor expression alteration in Alzheimer's disease (AD). However most of these findings have been obtained by using non-physiological Aβ concentrations. The present study deals with the effect of low Aβ concentrations on cellular homeostasis. We used nerve growth factor-differentiated PC12 cells and murine cortical neurons sequentially treated with low chronic monomeric or small oligomeric Aβ concentrations and high acute oligomeric Aβ concentrations to bring out a priming effect of chronic treatment on subsequently high Aβ concentrations-elicited cellular response. Both cell types indeed displayed an enhanced capacity to bind oligomeric Aβ after monomeric or small oligomeric Aβ application. Furthermore, the results show that monomeric Aβ1-42 application to the cells induces an increase of the Ca2+-response and of the membrane expression of the extrasynaptic subunit of the NMDA receptor GluN2B in PC12 cells, while the opposite effects were observed in cultured neurons. This suggests a sequential interaction of Aβ with the cellular plasma membrane involving monomers or small Aβ oligomers which would facilitate the binding of the deleterious high molecular Aβ oligomers. This mechanism would explain the slow progression of AD in the human nervous system and the deep gradient of neuronal death observed around the amyloid plaques in the nervous tissue.
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http://dx.doi.org/10.3233/JAD-142529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923730PMC
July 2016

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons.

Eur J Hum Genet 2016 May 5;24(5):710-6. Epub 2015 Aug 5.

Department of Genetics, Rouen University Hospital, Rouen, France.

Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.
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http://dx.doi.org/10.1038/ejhg.2015.173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930083PMC
May 2016

Can the syndrome of transient epileptic amnesia be the first feature of Alzheimer's disease?

Seizure 2014 Nov 18;23(10):918-20. Epub 2014 Jul 18.

Unité de Neuropsychologie, Service de Neurologie des Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Centre Mémoire, de Ressources et de Recherche d'Alsace (Strasbourg-Colmar), France; Laboratoire ICube, CNRS-Université de Strasbourg, France; Centre de Compétences des démences rares des Hôpitaux Universitaires de Strasbourg, France.

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http://dx.doi.org/10.1016/j.seizure.2014.07.008DOI Listing
November 2014

Impaired mental simulation of specific past and future personal events in non-depressed multiple sclerosis patients.

J Neurol Sci 2014 Oct 10;345(1-2):68-74. Epub 2014 Jul 10.

Cognitive Neuropsychology and Physiopathology of Schizophrenia (INSERM U 1114), University of Strasbourg, Strasbourg, France. Electronic address:

The aims of the present study were (i) to explore autobiographical memory and episodic future thought in multiple sclerosis (MS), using Levine's Autobiographical Interview; (ii) to investigate the influence of the Interview's high retrieval support condition (the specific probe phase) on MS patients' past and future simulations and (iii) to obtain the patients' estimations of their own difficulties, during the test, and in everyday life. To that end, we examined 39 non-depressed relapsing-remitting MS patients and 34 healthy subjects matched for gender, age and education level. The 73 participants underwent an adapted version of the Autobiographical Interview in two conditions: remembering and imagining personal events. The group of patients also underwent an extended neuropsychological baseline, including particularly, anterograde memory and executive functions. The results showed that the MS patients' scores on the baseline were mildly or not impaired. On the contrary, the Autobiographical Interview measure, i.e., the mean number of internal details, for each of the two phases of the test - free recall and specific probe - was significantly lower in simulated past and future events in comparison with the healthy controls. Within each group, autobiographical memory performance was superior to episodic future thought performance. A strong positive correlation was observed between past and future mental simulation scores in both groups. In conclusion, our results showed, for the first time, the co-occurrence of deficit of remembering the past and imagining the future in MS patients. They also showed more difficulty in imagining future events than remembering past events for both patients and normal controls. MS being a neurological condition very frequent in the young adult population, the clinical considerations of our study might be of interest. Indeed, they give rise to new insights on MS patients' daily life difficulties related to impaired mental simulation of personal events despite general abilities, including anterograde memory, only mildly or not impaired.
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http://dx.doi.org/10.1016/j.jns.2014.07.007DOI Listing
October 2014

Lyme neuroborreliosis and dementia.

J Alzheimers Dis 2014 ;41(4):1087-93

University Hospital of Strasbourg, Neuropsychology Unit, Neurology Service, Strasbourg, France INSERM U119, Strasbourg, France.

Introduction: Descriptions of Lyme disease and dementia are rare.

Objective: To describe patients with dementia and a positive "intrathecal anti-Borrelia antibody index" (AI), specific for neuroborreliosis.

Methods: Among 1,594 patients seen for dementia, we prospectively identified and studied 20 patients (1.25%) with dementia and a positive AI. Patients underwent a battery of neuropsychological tests brain, MRI, FDG-PET, and cerebrospinal fluid (CSF) analysis. An etiological diagnosis of the dementia was made at the end of the follow-up of 5.0 ± 2.9 years.

Results: We found two groups of patients with dementia, the first (n = 7, 0.44%) with certain neuroborreliosis and stability or mild improvement of dementia after treatment by antibiotics and the second (n = 13, 0.81%) with progressive worsening of dementia, despite the antibiotics. In the second group, the final diagnoses were Alzheimer's disease (AD) (n = 4), AD and Lewy body disease (LBD) (n = 3), LBD (n = 1), FTLD (n = 3), hippocampal sclerosis (n = 1), and vascular dementia (n = 1). We did not observe any differences in cognitive test between the two patient groups at baseline. Brain MRI showed more focal atrophy and FDG-PET showed more frontal hypometabolism in the second group. Tau, p-tau, and Aβ42 concentrations in the CSF were normal in the neuroborreliosis group, and coherent with diagnosis in the second.

Conclusion: Pure Lyme dementia exists and has a good outcome after antibiotics. It is advisable to do Lyme serology in demented patients, and if serology is positive, to do CSF analysis with AI. Neurodegenerative dementia associated with positive AI also exists, which may have been revealed by the involvement of Borrelia in the CNS.
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http://dx.doi.org/10.3233/JAD-130446DOI Listing
March 2015

Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomised, double-blind, placebo-controlled trial.

Lancet Neurol 2014 Feb 8;13(2):150-8. Epub 2014 Jan 8.

IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy. Electronic address:

Background: Creutzfeldt-Jakob disease (CJD) is a fatal, untreatable prion encephalopathy. Previous studies showed that doxycycline is effective in in-vitro and in-vivo models of disease, and patients with CJD who received compassionate treatment with doxycycline showed increased survival time compared with historical series. We therefore did a randomised, double-blind study of doxycycline versus placebo in CJD.

Methods: We recruited patients older than 18 years old who had a diagnosis of definite or probable sporadic CJD or genetic forms of the disease via Italian reference centres and the French national referral system. Patients were randomly assigned (ratio 1:1) to receive oral doxycycline (100 mg daily) or placebo under double-blind conditions from the day of randomisation to death. Centralised randomisation was done independently of enrolment or evaluation of patients using a minimisation method in Italy and a simple randomisation in France. Participants, caregivers, and clinicians were masked to group assignment. The primary efficacy variable was the survival time from randomisation. Interim analyses were planned to detect a significant effect of treatment as early as possible. This trial is registered with EudraCT, 2006-001858-27 for the Italian study and 2007-005553-34 for the French study.

Findings: From April 12, 2007, to Aug 19, 2010, in Italy, and from Jan 30, 2009, to Jan 10, 2012, in France, 121 patients with CJD were enrolled in the study, 62 of whom were randomly assigned to the treatment group and 59 to the placebo group. The first interim analysis showed absence of superiority of doxycycline compared with placebo, and the trial was stopped for futility. Efficacy analyses did not show significant differences between patients treated with doxycycline and placebo with regard to survival times (HR 1.1, 95% CI 0.8-1.7, p=0.50). Serious adverse events were judged not to be related to treatment, whereas a relation was deemed probable or possible for five non-serious adverse events that occurred in each treatment group.

Interpretation: Doxycycline at a dose of 100 mg per day was well tolerated but did not significantly affect the course of CJD, at variance with the results of previous observational studies. Our experience could be useful in the design of large multinational controlled trials of potential anti-prion molecules in this rare disease.

Funding: Agenzia Italiana Farmaco, Italian Ministry of Health, AIEnP, and French Ministry of Health.
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http://dx.doi.org/10.1016/S1474-4422(13)70307-7DOI Listing
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

Induced brain plasticity after a facilitation programme for autobiographical memory in multiple sclerosis: a preliminary study.

Mult Scler Int 2012 18;2012:820240. Epub 2012 Oct 18.

Imaging and Cognitive Neurosciences Laboratory (CNRS UMR 7237, IFR 037), University of Strasbourg, 12 rue Goethe, 67000 Strasbourg, France.

This preliminary study tackles the assessment and treatment of autobiographical memory (AbM) in relapsing-remitting multiple sclerosis (RR-MS) patients. Our aim was to investigate cerebral activation changes, following clinical improvement of AbM due to a cognitive training based on mental visual imagery (MVI). We assessed AbM using the Autobiographical Interview (AI) in eight patients and 15 controls. The latter subjects established normative data. The eight patients showed selective defective performance on the AI. Four patients were trained cognitively and underwent pre- and post-AI and fMRI. The remaining four patients took a second AI, at the same interval, but with no intervention in between. Results showed a significant improvement of AbM performance after the facilitation programme that could not be explained by learning effects since the AI scores remained stable between the two assessments in the second group of patients. As expected, AbM improvement was accompanied by an increased cerebral activity in posterior cerebral regions in post-facilitation fMRI examination. We interpret this activation changes in terms of reflecting the emphasis made on the role of MVI in memory retrieval through the facilitation programme. These preliminary significant clinical and neuroimaging changes suggest the beneficial effects of this technique to alleviate AbM retrieval deficit in MS patients.
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http://dx.doi.org/10.1155/2012/820240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483777PMC
November 2012