Eloi Magnin

Familial cortical myoclonic tremor with epilepsy The third locus (FCMTE3) maps to 5p

Background: Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by autosomal dominant adult-onset cortical myoclonus (CM) and seizures in 40% of patients. Two loci, 8q23.3-q24.11 (FAME1/FCMTE1) and 2p11.1-q12.2 (FAME2/FCMTE2), were previously reported without an identified gene. Unlinked families argue for a third mutated gene. Methods: A genome-wide scan was performed in a large FCMTE family using Linkage-12 microarrays (Illumina). Refinement of the locus on 5p was performed by genotyping 13 polymorphic microsatellite markers in the 45 available family members. Results: This large French FCMTE family included 16 affected relatives. The first symptoms were CM in 5 patients (31.2%), seizures in 5 patients (31.2%), and both at the same time in 6 patients (37.5%). A total of 12.5% (2/16) had only CM without seizures. The genome-wide scan identified a single region on 5p15.31-p15, with a multipoint lod score of 3.66. Further genotyping of all family members confirmed that the region spans 9.31 Mb between D5S580 and D5S2096, 2-point lod scores reaching 6.3 at θ = 0 for D5S486. Sequencing of the SEMA5A and CTNND2 genes failed to detect mutations. Conclusions: We report the clinical and genetic characteristics of a large familial cortical myoclonic tremor with epilepsy family. The third gene maps to 5p15.31-p15. Identification of the mutated gene is ongoing.

A case report of daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) as an adjunctive treatment for Alzheimer disease

Department of Clinical Psychiatry, University Hospital of Besancon, France EA 481 Neuroscience, IFR 133, University of Franche-Comt e, Besancon, France Clinical Investigation Center CIC-IT 808 INSERM, University Hospital of Besancon, France Department of Neurology, University Hospital of Besancon, France Memory Center of Research and Resources (MCRR), University Hospital of Besancon, France Rapid-Fr Network (Regional Network for Diagnostic Aid and Management of patients with Cognitive Impairment in the Franche-Comt e geographical area), Besancon, France

Olfactory Dysfunction in Multiple Sclerosis: Evidence of a Decrease in Different Aspects of Olfactory Function

Background/Aims: Numerous authors have described olfactory dysfunction in multiple sclerosis (MS) in recent years. The aim of this study was to specify the aspects of olfactory perception that are most affected and to identify any correlations with clinical, anatomical and functional data. Methods: 50 patients with remitting or secondary progressive MS were included. Personal data were collected (medical history, characteristics of their disease, depression and disability scores and number of lesions on cerebral imaging). An olfactory test (Sniffin Sticks®) was used to evaluate subjects’ olfactory function. Results: The odor detection threshold is the most sensitive marker, with 40% of patients presenting hyposmia. The ability to identify odors is affected later on, and is inversely correlated with the level of disability. Conclusion: Our results confirm that several aspects of olfactory function are altered in MS, particularly those aspects requiring greater cognitive involvement, such as discrimination and identification of odors.

Logopenic syndrome in posterior cortical atrophy

Few language disorders have been reported in posterior cortical atrophy (PCA). Furthermore, no study has focused on screening for them and described these language deficits. The goal of this work was to describe linguistic examination of PCA patients and the impact of language disorders on neuropsychological performances compared to patients with other neurodegenerative syndromes and control groups. Linguistic examination of 9 PCA patients was carried out. The neuropsychological performance of the PCA group (16 patients) in the RAPID battery tests was compared with performances of patients with a logopenic variant of primary progressive aphasia (LPPA), patients with Alzheimer’s disease and patients with amnestic mild cognitive impairment, as well as the control group. A “logopenic syndrome” with anomia, fluency impairment, and length-dependent deficit was found in 8/9 PCA patients. A comparison with other neurodegenerative syndromes showed that not only visual disorders but also language and verbal short-term memory disorders, such as those found in LPPA, can explain neuropsychological performances. A “logopenic syndrome” is frequently found in PCA and may be associated with poor performance on other verbally mediated neuropsychological tasks (e.g., verbal memory). Specific logopedic rehabilitation should be offered to these patients.

Bipolar disorder and dementia: where is the link?

Cognitive disorders appearing in the course of bipolar disease have been identified, and recent studies have defined the neuropsychological characteristics of this pathology, which includes attention, executive function, memory and language disorders. However, questions remain concerning the appearance of dementia symptoms over the course of bipolar disorder in certain patients: is it a chance association or is there a connection between bipolar disorders and dementia? If the latter hypothesis is considered, what is the nature of the dementia, which might be considered as a dementia specific to bipolar disorder? Current clinical, neuropsychological and cerebral imaging data are inconclusive, but similarities with frontotemporal dementia might be highlighted. Functional imaging studies might provide answers as well as more specific tests in neuropsychology. The cause of cognitive damage in bipolar disease also raises questions concerning a neurodevelopmental or neurodegenerative process, because several factors seem to influence cognition and these two processes might occur simultaneously. Long‐term studies are necessary to determine whether cognitive deterioration in bipolar disease is stable or progressive. There might also be different neurobiological subgroups of patients with bipolar disease.

Initial neuropsychological profile of a series of 20 patients with logopenic variant of primary progressive aphasia.

BACKGROUND Logopenic variant of primary progressive aphasia (LPPA) is classically considered as an isolated language disorder, but verbal short-term memory deficit induces difficulties in neuropsychological tests that are not intended to evaluate language. OBJECTIVE The aim of this study is to describe the initial symptoms and neuropsychological profiles of LPPA. METHODS A retrospective study was conducted with a series of 20 consecutive patients diagnosed with LPPA. Clinical, neuroimaging, neuropsychological, and linguistic examinations are reported. The first neuropsychological examinations (mean time between neuropsychological assessment and diagnosis: 11 months) were then compared to 20 patients with mild cognitive impairment (MCI) and 20 patients with Alzheimers disease (AD) matched by age, gender, and education level. RESULTS A recent onset or aggravation of anxiety disorders was frequently reported. An unusual neuropsychological profile, different from that of AD or MCI, was observed: dissociation between verbal and visual memory performances, poor encoding performances on verbal memory tests, and preserved orientation to time, difficulties with mental calculation and fluency tasks. Biparetal abnormality and left hippocampal diaschisis was frequently observed. Asymptomatic dopaminergic depletion was observed in four patients. CONCLUSION Our study identifies that de novo or recently worsening anxiety and specific neuropsychological profiles call for screening for LPPA, including a linguistic examination. Sometimes, there may be a continuum between LPPA and corticobasal syndrome.

Normes diagnostiques de la batterie de tests neuropsychologiques RAPID pour les sujets âgés de 60 à 89 ans présentant une maladie d’Alzheimer

INTRODUCTION The aim of this study was to propose diagnostic norms for the rapid neuropsychological battery, in the detection of cognitive impairment due to Alzheimers disease. POPULATION AND METHODS Three hundred and fifty-two control subjects (mean MMSE : 27.3 ± 2.5) and 676 patients with Alzheimers disease (mean MMSE : 22.9 ± 2.6) at a mild stage (CDR = 1) were selected according to age (60-69, 70-79 and 80-89 years) and educational level (French primary Education Certificate or lower versus Certificate of Professional Aptitude or the School Leaving Certificate versus the Baccalaureate or higher). Age and education-adjusted cut-off scores were calculated using Receiver Operating Characteristic curves so as to determine the discriminative ability (sensitivity, specificity) of each test from the RAPID neuropsychological battery. Cut-off scores with a specificity set at least at 90% were also proposed. RESULTS The Free and Cued Recall Test exhibited good sensitivity (from 87% to 100% for free recall and from 85% to 98% for total recall) and specificity (from 85% to 96% for free recall and from 86% to 100% for total recall). For the other tests, sensitivities and specificities were lower. CONCLUSION The use of these two types of cut-off scores should help the clinician in the diagnosis of Alzheimers disease by limiting the risk of false positives and false negatives. The choice of the cut-off scores will depend on the patients individual clinical context.

Familial cortical myoclonic tremor with epilepsy (FCMTE): Clinical characteristics and exclusion of linkages to 8q and 2p in a large French family

INTRODUCTION Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by an autosomal-dominant inheritance, adult onset of myoclonus of the extremities, infrequent epileptic seizures, a non-progressive course, polyspikes on electroencephalography (EEG), photosensitivity, giant somatosensory-evoked potentials (SEP), enhancement of C-reflex and a premyoclonus spike detected by jerk-locked EEG back-averaging. Two genes yet to be identified are mapped to 8q23.3-q24.1 and 2p11.1-q12.2. METHODS The present study involved five generations of a French family presenting with FCMTE, including 76 family members. Clinical analyses were performed in 39 living subjects and electrophysiological studies in five patients. Altogether, 27 relatives (21 living and six deceased) had the clinical characteristics of FCMTE, 17 of whom were analyzed. Linkage analyses were performed with microsatellites encompassing the two known loci (8q 23.3-q24.1 and 2p11.1-q12.2). RESULTS Mean age at onset in the 17 living patients was 28.8 years (range 24-41). All had myoclonus/cortical tremor, and 11/17 had generalized tonic-clonic seizures. Other clinical symptoms were photosensitivity (16 cases), partial seizures (five cases), sensitivity to starvation/exercise (six cases) and vibration (four cases), ophthalmic migraine (six cases) and gait disorders (10 cases). Electrophysiological studies confirmed the FCMTE diagnosis in the five studied patients. Of the remaining relatives, 14 were considered healthy (asymptomatic subjects aged more than 40years) and eight were of unknown status (asymptomatic aged lesser than 40years). The pattern of inheritance was consistent with autosomal-dominant inheritance, although the two loci responsible for FCMTE were excluded. CONCLUSION This large family highlights some unusual clinical characteristics and suggests the presence of a third gene. Genetic research is ongoing to identify the mutated gene.

Increased Cerebrospinal Fluid Tau Levels in Logopenic Variant of Alzheimer's Disease

BACKGROUND Patients with logopenic variant of primary progressive aphasia (lvPPA) display neuropathological differences from typical amnestic Alzheimers disease (AD). OBJECTIVE The aim of the study was to compare cerebrospinal fluid (CSF) biomarker levels between patients with lvPPA due to AD (lvPPA-AD), non-logopenic forms of AD (nlAD), and amnestic mild cognitive impairment due to AD (aMCI-AD). METHODS CSF biomarker concentrations were assessed in 124 patients divided into three groups matched for age, level of education, center, and disease duration: lvPPA-AD (n = 30), nlAD (n = 67). and aMCI-AD (n = 27). RESULTS p-Tau181 levels were higher in the lvPPA-AD group than in the aMCI-AD group (p < 0.05). Total tau levels were higher in the lvPPA-AD group versus those in the nlAD (p < 0.05) and aMCI-AD (p < 0.001) groups. CONCLUSIONS These results suggest a more pronounced involvement of a taupathy in lvPPA-AD compared to aMCI-AD and a more important neuronal death in lvPPA-AD than in nlAD or aMCI-AD.

Fractional Anisotropy in Three Variants of Primary Progressive Aphasia

Objective: Our aim was to report diffusion tensor imaging (DTI) patterns in three patients, each with a different primary progressive aphasia (PPA) variant. Design: One agrammatic PPA, one semantic PPA, and one logopenic PPA subject underwent a magnetic resonance imaging examination including DTI sequences. The fractional anisotropy (FA) value was calculated in regions of interest (ROIs) involved in these three variants (perisylvian region, temporal pole, and parietotemporal junction) for each patient. Left-right FA ratios in each ROI were compared between PPA subjects and a group of three amnestic mild cognitive impairment patients with a cerebrospinal fluid biomarker profile of the Alzheimer type. Results: The FA values were lower in the left hemisphere (p = 0.03). The lowest FA values were observed in the left perisylvian region for the non-fluent/agrammatic subtype PPA patient, in the left anterior temporal lobe for the semantic subtype PPA patient, and in the left parietotemporal junction for the logopenic patient (p = 0.028). The left-right FA ratio in these specific ROIs for each PPA variant was significantly lower than in the amnestic mild cognitive impairment group (p = 0.009). Conclusion: DTI patterns could be an effective new tool for diagnosing PPA and classifying the three variants.