Catherine Martin-Hunyadi

Cortical Thickness in Dementia with Lewy Bodies and Alzheimer's Disease: A Comparison of Prodromal and Dementia Stages

Objectives To assess and compare cortical thickness (CTh) of patients with prodromal Dementia with Lewy bodies (pro-DLB), prodromal Alzheimers disease (pro-AD), DLB dementia (DLB-d), AD dementia (AD-d) and normal ageing. Methods Study participants(28 pro-DLB, 27 pro-AD, 31 DLB-d, 54 AD-d and 33 elderly controls) underwent 3Tesla T1 3D MRI and detailed clinical and cognitive assessments. We used FreeSurfer analysis package to measure CTh and investigate patterns of cortical thinning across groups. Results Comparison of CTh between pro-DLB and pro-AD (p<0.05, FDR corrected) showed more right anterior insula thinning in pro-DLB, and more bilateral parietal lobe and left parahippocampal gyri thinning in pro-AD. Comparison of prodromal patients to healthy elderly controls showed the involvement of the same regions. In DLB-d (p<0.05, FDR corrected) cortical thinning was found predominantly in the right temporo-parietal junction, and insula, cingulate, orbitofrontal and lateral occipital cortices. In AD-d(p<0.05, FDR corrected),the most significant areas affected included the entorhinal cortices, parahippocampal gyri and parietal lobes. The comparison of AD-d and DLB-d demonstrated more CTh in AD-d in the left entorhinal cortex (p<0.05, FDR corrected). Conclusion Cortical thickness is a sensitive measure for characterising patterns of grey matter atrophy in early stages of DLB distinct from AD. Right anterior insula involvement may be a key region at the prodromal stage of DLB and needs further investigation.

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

BACKGROUNDnAside 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.nnnOBJECTIVEnThe objective of this study was to verify the existence and the syndromic features of epileptic prodromal AD in a tertiary Memory Clinic.nnnMETHODSnWe 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, nu200a=u200a430 subjects), selected on both clinical criteria and CSF biomarkers.nnnRESULTSnIn 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).nnnCONCLUSIONnOur 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.

Grey matter atrophy in prodromal stage of dementia with Lewy bodies and Alzheimer's disease

BackgroundLittle is known about the patterns of brain atrophy in prodromal dementia with Lewy bodies (pro-DLB).MethodsIn this study, we used SPM8 with diffeomorphic anatomical registration through exponentiated lie algebra to measure grey matter (GM) volume and investigate patterns of GM atrophy in pro-DLB (nu2009=u200928) and prodromal Alzheimer’s disease (pro-AD) (nu2009=u200927) and compared and contrasted them with those in elderly control subjects (nu2009=u200933) (Pu2009≤u20090.05 corrected for family-wise error).ResultsPatients with pro-DLB showed diminished GM volumes of bilateral insulae and right anterior cingulate cortex compared with control subjects. Comparison of GM volume between patients with pro-AD and control subjects showed a more extensive pattern, with volume reductions in temporal (hippocampi and superior and middle gyri), parietal and frontal structures in the former. Direct comparison of prodromal groups suggested that more atrophy was evident in the parietal lobes of patients with pro-AD than patients with pro-DLB. In patients with pro-DLB, we found that visual hallucinations were associated with relative atrophy of the left cuneus.ConclusionsAtrophy in pro-DLB involves the insulae and anterior cingulate cortex, regions rich in von Economo neurons, which we speculate may contribute to the early clinical phenotype of pro-DLB.

Diagnostic Value of Cerebrospinal Fluid Biomarkers (Phospho-Tau181, total-Tau, Aβ42, and Aβ40) in Prodromal Stage of Alzheimer's Disease and Dementia with Lewy Bodies.

BACKGROUNDnDementia with Lewy bodies (DLB) symptoms are close to those of Alzheimers disease (AD), and the differential diagnosis is difficult especially early in the disease. Unfortunately, AD biomarkers in cerebrospinal fluid (CSF), and more particularly Aβ1xa0-xa042, appear to be altered in dementia with Lewy bodies (DLB). However, the level of these biomarkers has never been studied in the prodromal stage of the disease.nnnOBJECTIVEnTo compare these biomarkers between DLB and AD, with a particular focus on the prodromal stage.nnnMETHODSnA total of 166 CSF samples were collected at the memory clinic of Strasbourg. They were obtained from prodromal DLB (pro-DLB), DLB dementia, prodromal AD (pro-AD), and AD dementia patients, and elderly controls. Phospho-Tau181, total-Tau, Aβ42, and Aβ40 were measured in the CSF.nnnRESULTSnAt the prodromal stage, contrary to AD patients, DLB patients biomarker levels in the CSF were not altered. At the demented stage of DLB, Aβ42 levels were reduced as well as Aβ40 levels. Thus, the Aβ42/Aβ40 ratio remained unchanged between the prodromal and demented stages, contrary to what was observed in AD. Tau and Phospho-Tau181 levels were unaltered in DLB patients.nnnCONCLUSIONSnWe have shown that at the prodromal stage the DLB patients had no pathological profile. Consequently, CSF AD biomarkers are extremely useful for differentiating AD from DLB patients particularly at this stage when the clinical diagnosis is difficult. Thus, these results open up new perspectives on the interpretation of AD biomarkers in DLB.

Cognitive and affective theory of mind in dementia with Lewy bodies and Alzheimer’s disease

BackgroundTheory of mind (ToM) refers to the ability to attribute mental states, thoughts (cognitive component) or feelings (affective component) to others. This function has been studied in many neurodegenerative diseases; however, to our knowledge, no studies investigating ToM in dementia with Lewy bodies (DLB) have been published. The aim of our study was to assess ToM in patients with DLB and to search for neural correlates of potential deficits.MethodsThirty-three patients with DLB (DLB group) and 15 patients with Alzheimer’s disease (AD group), all in the early stage of the disease, as well as 16 healthy elderly control subjects (HC group), were included in the study. After a global cognitive assessment, we used the Faux Pas Recognition (FPR) test, the Reading the Mind in the Eyes (RME) test and Ekman’s Facial Emotion Recognition test to assess cognitive and affective components of ToM. Patients underwent cerebral 3-T magnetic resonance imaging, and atrophy of grey matter was analysed using voxel-based morphometry. We performed a one-sample t test to investigate the correlation between each ToM score and grey matter volume and a two-sample t test to compare patients with DLB impaired with those non-impaired for each test.ResultsThe DLB group performed significantly worse than the HC group on the FPR test (Pu2009=u20090.033) and the RME test (Pu2009=u20090.015). There was no significant difference between the AD group and the HC group or between the DLB group and the AD group. Some brain regions were associated with ToM impairments. The prefrontal cortex, with the inferior frontal cortex and the orbitofrontal cortex, was the main region, but we also found correlations with the temporoparietal junction, the precuneus, the fusiform gyrus and the insula.ConclusionsThis study is the first one to show early impairments of ToM in DLB. The two cognitive and affective components both appear to be affected in this disease. Among patients with ToM difficulties, we found atrophy in brain regions classically involved in ToM, which reinforces the neuronal network of ToM. Further studies are now needed to better understand the neural basis of such impairment.

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

Transient epileptic amnesia (TEA) is a specific type of temporal lobe seizure involving the hippocampus and the parahippocampal gyrus, which can be recognized with now published criteria. The etiology of TEA is still under debate and probably not unique. Apart from rare patients showing structural lesions on brain MRI, microvascular brain load and/or immune-mediated neuronal aggression have been proposed as alternative causes. A neurodegenerative process is also possible, as suggested by decreased hippocampal volume and ongoing memory complaints despite seizure freedom in many treated subjects. Thus, late onset Alzheimer’s disease (LOAD) logically appears as a potential cause of TEA. Indeed, we present a case of TEA that secondarily evolved into AD 16 years after seizures onset. The patient was right-handed and had 9 years of education. She had no remarkable medical history. Her mother had been diagnosed with LOAD at the age of 70. The patient was 64 when she came in 2009 to our Memory Clinic for cognitive complaints developing since her first transient antero-retrograde amnesia (in 1994) that lasted about 10 h and started with a preceding aura (ascending thoraco-abdominal pain with diffuse heat sensation and nausea) while witnesses described contact loss for 2 min, bilateral arm dystonia and oral automatisms (tongue smacking). Transient global amnesia (TGA) was diagnosed because screening blood tests, brain CT scan and EEG were all within the normal range. In 1994, her MMSE score was 30/30, even though she was complaining of abnormal long term forgetting and autobiographical difficulties (she did not remember her wedding or several vacations during the previous 10 years). Another antero-retrograde amnesia occurred 5 years later (1999), which lasted 2 h and was preceded by the same aura and a sudden fall. Witnesses again described partial contact loss during amnesia. CT-scan and EEG were still normal as was the cardiovascular work-up. Thereafter, the patient became depressed and the subjective cognitive

Insular atrophy at the prodromal stage of dementia with Lewy bodies: a VBM DARTEL study

Diffuse atrophy including the insula was previously demonstrated in dementia with Lewy bodies (DLB) patients but little is known about the prodromal stage of DLB (pro-DLB). In this prospective study, we used SPM8-DARTEL to measure gray matter (GM) and white matter (WM) atrophy in pro-DLB patients (nu2009=u200954), prodromal Alzheimer’s disease (pro-AD) patients (nu2009=u200916), DLB patients at the stage of dementia (mild-DLB) (nu2009=u200915), and Alzheimer’s disease patients at the stage of dementia (mild-AD) (nu2009=u200928), and compared them with healthy elderly controls (HC, nu2009=u200922). Diminished GM volumes were found in bilateral insula in pro-DLB patients, a trend to significance in right hippocampus and parahippocampal gyrus in pro-AD patients, in left insula in mild-DLB patients, and in medial temporal lobes and insula in mild-AD patients. The comparison between prodromal groups did not showed any differences. The comparison between groups with dementia revealed atrophy around the left middle temporal gyrus in mild-AD patients. Reduced WM volume was observed in mild-DLB in the pons. The insula seems to be a key region in DLB as early as the prodromal stage. MRI studies looking at perfusion, and functional and anatomical connectivity are now needed to better understand the role of this region in DLB.

Do we know how to diagnose epilepsy early in Alzheimer's disease?

Epilepsy is an increasingly recognized comorbidity in Alzheimers disease (AD). First described as generalized in dementia patients, epileptic AD patients are nowadays fully described in earlier stages of the disease (with mild or subjective cognitive impairment). At such early stages, patients may present not only with generalized seizures, but also with focal seizures (commonly localized in the frontal or temporal lobe). Thus, partial or generalized epilepsy is part of the semiological spectrum of AD that should be borne in mind at all stages of disease to ensure early identification and prevent the risk of repeated seizures (such as accidents, injury, progression of cognitive impairment). This review of the available (and still growing) literature shows that there are already sufficient data to inform physicians on seizure semiology, and on the diagnostic value of electroencephalography and brain imaging. Taken together, these tools can help to rapidly identify epilepsy in AD patients. Nevertheless, epilepsy diagnosis can be challenging, and test medication is sometimes necessary. Some cerebrospinal fluid biomarkers (or their ratios) may also prove to be good predictors of seizures in AD, but further studies are needed. Epilepsy in AD patients is frequently pharmacosensitive, and a good response can be obtained with standard doses of antiepileptic drugs. For all these reasons and based on our review of the literature, it appears that, at present, the diagnosis of epilepsy in AD is not only possible at any stage of the disease, but also to be recommended to improve the patients prognosis.

PRODROMAL AND NON-PRODROMAL DEMENTIA WITH LEWY BODIES AND ALZHEIMER'S DISEASE: A MULTIMODAL MRI APPROACH

2011); 17/41 (41%) had onset after and 24/41 (59%) before 65 years. We compared clinical, radiological, and CSF data at the initial valuation. Results: Late-onset bvFTLD (mean age at onset: 7063 years; probable bvFTLD1⁄459%) and presenile-onset bvFTLD (mean age at onset 5965 years; probable bvFTLD1⁄471%) had comparable mean disease duration at initial examination (363 years) and mean follow up duration (563 vs 564 years). MRI examination confirmed more frequent hippocampal atrophy (47% vs 21%) and less lobar atrophy (18% vs 58%) in late-onset bvFTLD; this was clinically correlated to more frequent hippocampal memory deficit (53% vs 12.5%). TEP-FDG or SPECT-HMPAO imaging detected focal hypometabolism/hypoperfusion in 53% vs 62.5% of the patients. Unexpectedly, no differences were found in CSF abeta1-42 (10976276 vs 10346236), T-tau (2896214 vs 2316100), P-tau (40617 vs 37615), and IATI index (260.6 vs 260.6); the ratio T-tau/abeta1-42 (0.2660.16 vs 0.2360.10) and P-tau/abeta1-42 (0.0460.01 vs 0.0460.01) were not different, either. In each group three subjects had high T-tau or P-Tau and one subject low abeta1-42. Conclusions:Late-onset bvFTLD is not rare in clinical practice; we confirmed more hippocampal and global atrophy compared to presenile-onset bvFTLD, clinically correlated to more frequent hippocampal memory loss. TEP-FDG and SPECT-HMPAO focal alterations were equally represented. Since no differences were found in CSF biomarkers, the differences between lateand presenile-onset bvFTLD could not be explained by co-existing AD pathology in older patients. They could instead be due to hippocampal sclerosis, known to be associated to FTLD. These data suggest the potential interest of CSF and metabolic markers in the differential diagnosis of late-onset bv-FTLD vs AD.

Les biomarqueurs conventionnels de la maladie d’Alzheimer dans le LCR (Abeta42, Tau, Phospho-Tau) ne sont pas pathologiques chez les patients au stade prodromal d’une démence à Corps de Lewy

Introduction La demence a Corps de Lewy (DCL) est la seconde demence la plus frequente apres la maladie d’Alzheimer (MA). Le diagnostic differentiel est particulierement difficile entre ces deux maladies au stade prodromal. Objectifs Notre objectif est d’etudier les niveaux des biomarqueurs classiques de la MA dans le LCR de ces deux groupes, a differents stades de la pathologie pour determiner la pertinence de ceux-ci dans le diagnostic differentiel. Methodes Les patients ont ete classes selon les criteres de McKeith pour les patients DCL et les criteres de Dubois pour les patients Alzheimer. Les resultats de la ponction lombaire n’ont pas ete pris en compte pour la classification des patients. Les patients ont ete categorises selon leur pathologiexa0: MA, DCL, ou MAxa0+xa0DCL mais egalement en fonction de leur stade de demence (prodromal ou dement). Nous avons ensuite analyse et compare les resultats de leurs biomarqueurs. Resultats Pour les patients DCL dements, nous avons trouve une diminution isolee d’Abeta42 dans leur LCR, equivalente a celle retrouvee chez les patients MA. Les niveaux des proteines Tau et Phospho-Tau sont quant a eux identiques a ceux retrouves chez les patients controles. Ces resultats sont conformes a ce qui a ete decrit dans la litterature. Cependant, au stade prodromal, les patients DCL ne presentent pas de diminution d’Abeta42 et ainsi l’ensemble de leur profil est identique a celui des patients controles. Discussion Le niveau de ces biomarqueurs n’avait jamais ete etudie auparavant chez des patients DCL a un stade prodromal. Ainsi, nous avons pu montrer pour la premiere fois que des patients au stade prodromal de DCL ne presentent pas de profil biochimique (Abeta42, Tau et Phospho-Tau) pathologique. Par contre ce profil evolue au stade dementiel avec une diminution de l’Abeta42 chez ces patients. Conclusion Ainsi au stade prodromal, a un moment ou le diagnostic differentiel entre les deux pathologies est le plus difficile, les biomarqueurs conventionnels de la MA permettent de faire ce diagnostic differentiel.