%0 Journal Article %J J Alzheimers Dis %D 2018 %T Influence of Lewy Pathology on Alzheimer's Disease Phenotype: A Retrospective Clinico-Pathological Study. %A Roudil, Jennifer %A Deramecourt, Vincent %A Dufournet, Boris %A Dubois, Bruno %A Ceccaldi, Mathieu %A Duyckaerts, Charles %A Pasquier, Florence %A Lebouvier, Thibaud %X

BACKGROUND: Studies have shown the frequent coexistence of Lewy pathology (LP) in Alzheimer's Disease (AD).

OBJECTIVE: The aim of this study was to determine the influence of LP on the clinical and cognitive phenotype in a cohort of patients with a neuropathological diagnosis of AD.

METHODS: We reviewed neuropathologically proven AD cases, reaching Braak stages V and VI in the brain banks of Lille and Paris between 1993 and 2016, and classified them according to LP extension (amygdala, brainstem, limbic, or neocortical). We then searched patient files for all available clinical and neuropsychiatric features and neuropsychological data.

RESULTS: Thirty-three subjects were selected for this study, among which 16 were devoid of LP and 17 presented AD with concomitant LP. The latter were stratified into two subgroups according to LP distribution: 7 were AD with amygdala LP and 10 were AD with 'classical' (brainstem, limbic or neocortical) LP. When analyzing the incidence of each clinical feature at any point during the disease course, we found no significant difference in symptom frequency between the three groups. However, fluctuations appeared significantly earlier in patients with classical LP (2±3.5 years) than in patients without LP (7±1.7 years) or with amygdala LP (8±2.8 years; p < 0.01). There was no significant difference in cognitive profiles.

CONCLUSION: Our findings suggest that the influence of LP on the clinical phenotype of AD is subtle. Core features of dementia with Lewy bodies do not allow clinical diagnosis of a concomitant LP on a patient-to-patient basis.

%B J Alzheimers Dis %V 63 %P 1317-1323 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29758938?dopt=Abstract %R 10.3233/JAD-170914 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Low Prevalence and Clinical Effect of Vascular Risk Factors in Early-Onset Alzheimer's Disease. %A Chen, Yaohua %A Sillaire, Adeline Rollin %A Dallongeville, Jean %A Skrobala, Emilie %A Wallon, David %A Dubois, Bruno %A Hannequin, Didier %A Pasquier, Florence %X

BACKGROUND: Determinants of early-onset Alzheimer's disease (EOAD) are not well known. In late-onset AD, vascular risk factors (VRFs) are associated with earlier clinical manifestation.

OBJECTIVE: The objective of this study was to assess the putative association between VRFs and EOAD.

METHODS: We studied participants with dementia meeting criteria for EOAD (recruited into the French CoMAJ prospective cohort study from 1 June 2009 to 28 February 2014) and age-, gender-matched controls (ratio 1:3, drawn randomly from the French MONA-LISA population-based survey between 2005 and 2007). Demographic data, VRFs, comorbidities, treatments, and APOE genotypes were compared in multivariable logistic regression analyses.

RESULTS: We studied 102 participants with dementia (mean±standard deviation age: 59.5±3.8; women: 59.8%) and 306 controls. Compared with controls, EOAD participants had spent less time in formal education (9.9±2.9 versus 11.7±3.8 y; p < 0.0001), were less likely to be regular alcohol consumers (p < 0.0001), had a lower body mass index (-2 kg/m2; p < 0.0004), and a lower mean systolic blood pressure (-6.2 mmHg; p = 0.0036). The prevalence of APOE ɛ4 allele was higher in participants with dementia than in controls (50% versus 29.4%; p = 0.0002), as was the prevalence of depression (48% versus 32%; p < 0.001). Similar results were observed in multivariable analysis. Compared with EOAD participants lacking VRFs, EOAD participants with at least one VRF had a higher prevalence of depression (29.6% versus 53.3%, respectively; p = 0.03).

CONCLUSION: The prevalence of VRFs is not elevated in EOAD patients (in contrast to older AD patients). Extensive genetic testing should be considered more frequently in the context of EOAD.

%B J Alzheimers Dis %V 60 %P 1045-1054 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28984595?dopt=Abstract %R 10.3233/JAD-170367 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Modeling the Distress of Spousal Caregivers of People with Dementia. %A Wawrziczny, Emilie %A Berna, Guillaume %A Ducharme, Francine %A Kergoat, Marie-Jeanne %A Pasquier, Florence %A Antoine, Pascal %X

BACKGROUND: The progressive mobilization of spouse caregivers who take care of a person with dementia (PWD) can lead to situations of distress.

OBJECTIVE: The current study sought to investigate the influence of the characteristics of the caregiving context on spousal caregiver distress.

METHODS: 125 spousal caregivers participated in this study. The characteristics of the caregiving context were assessed using questionnaires. We examined a moderated-mediator model (Step 1) in which we hypothesized that PWD and caregiver characteristics and dyadic determinants contribute to spousal caregiver distress. This model was compared based on the age at onset of the disease and the gender of the caregiver (Step 2).

RESULTS: The model revealed that poor self-rated health and a lack of family support accentuated spousal caregiver distress, whereas the feeling of being prepared and level of confidence decreased spousal caregiver distress. Moreover, the quality of couple adjustment affected spousal caregiver distress, and this effect was mediated by the severity of the PWD's symptoms. Regarding the age at onset of the disease, the path between Couple Adjustment and the Care recipient's impairments was more important for caregivers of person with early-onset dementia (PEOD). Female caregivers who reported poor self-rated health experienced greater distress.

CONCLUSIONS: It would be interesting to create a support program that would incorporate these three areas of intervention regarding the progression of the disease: first, "preparedness modules"; second, "dyadic modules" (especially for caregivers of PEOD); and third, "family modules". Specific attention should be given to female caregivers who report poor self-rated health.

%B J Alzheimers Dis %V 55 %P 703-716 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27716667?dopt=Abstract %R 10.3233/JAD-160558 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Diagnosis of Dementia with High Levels of Cerebrospinal Fluid Tau Protein. %A Grangeon, Lou %A Paquet, Claire %A Bombois, Stephanie %A Quillard-Muraine, Muriel %A Martinaud, Olivier %A Bourre, Bertrand %A Lefaucheur, Romain %A Nicolas, Gaël %A Dumurgier, Julien %A Gerardin, Emmanuel %A Jan, Mary %A Laplanche, Jean-Louis %A Peoc'h, Katell %A Hugon, Jacques %A Pasquier, Florence %A Maltête, David %A Hannequin, Didier %A Wallon, David %K Adult %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Creutzfeldt-Jakob Syndrome %K Dementia, Vascular %K Diagnosis, Differential %K Female %K France %K Frontotemporal Dementia %K Humans %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %K Phosphorylation %K Retrospective Studies %K Sex Factors %K tau Proteins %X

BACKGROUND: Total Tau concentration in cerebrospinal fluid (CSF) is widely used as a biomarker in the diagnosis of neurodegenerative process primarily in Alzheimer's disease (AD). A particularly high Tau level may indicate AD but may also be associated with Creutzfeldt-Jakob disease (CJD). In such situations little is known about the distribution of differential diagnoses.

OBJECTIVE: Our study aimed to describe the different diagnoses encountered in clinical practice for patients with dementia and CSF Tau levels over 1000 pg/ml. We studied the p-Tau/Tau ratio to specify its ability to distinguish AD from CJD.

METHODS: Patients (n = 202) with CSF Tau levels over 1000 pg/ml were recruited in three memory clinics in France. All diagnoses were made using the same diagnostic procedure and criteria.

RESULTS: Patients were diagnosed with AD (n = 148, 73.2%), mixed dementia (n = 38, 18.8%), CJD, vascular dementia (n = 4, 2.0% for each), Lewy body dementia, and frontotemporal dementia (n = 3, 1.5% for each). Dispersion of CSF Tau levels clearly showed an overlap between all diagnoses. Using the p-Tau/Tau ratio suggestive of CJD (<0.075), all CJD patients were correctly categorized and only two AD patients were miscategorized. This ratio was highly associated with CJD compared to AD (p < 0.0001).

CONCLUSION: Our study showed that in clinical practice, extremely high CSF Tau levels are mainly related to diagnosis of AD. CJD patients represent a minority. Our results support a sequential interpretation algorithm for CSF biomarkers in dementia. High CSF Tau levels should alert clinicians to check the p-Tau/Tau ratio to consider a probable diagnosis of CJD.

%B J Alzheimers Dis %V 51 %P 905-13 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890785?dopt=Abstract %R 10.3233/JAD-151111 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Limiting Factors of Brain Donation in Neurodegenerative Diseases: The Example of French Memory Clinics. %A Le Bouc, Raphael %A Marelli, Cecilia %A Beaufils, Emilie %A Berr, Claudine %A Hommet, Caroline %A Touchon, Jacques %A Pasquier, Florence %A Deramecourt, Vincent %K Autopsy %K Brain %K France %K Health Knowledge, Attitudes, Practice %K Humans %K Neurodegenerative Diseases %K Physicians %K Retrospective Studies %X

Postmortem neuropathological examination of the brain is essential in neurodegenerative diseases, to ensure accurate diagnosis, to obtain an a posteriori critical assessment of the adequacy of clinical care, and to validate new biomarkers, but is only rarely performed. The purpose of this study was to assess factors limiting brain donation, such as reluctance of physicians to seek donation consent, opposition from patients and families, and organizational constraints. We conducted a survey across French memory clinics and major neuropathological centers. Few postmortem examinations were performed annually, as less than one third of the centers had performed at least five autopsies, and 41% had performed none. The main limiting factor was the lack of donation requests made by physicians, as half of them never approach patients for brain donation. Reasons for not seeking donation consent often include discomfort broaching the subject and lack of awareness of the medical and scientific benefit of postmortems (77%), organizational constraints (61%), and overestimation of families' negative reaction (51%). Family refusals represented a second major obstacle, and were often caused by misconceptions. Identifying and addressing these biases early could help improve physicians' rate of making requests and the public's awareness about the importance of brain donation.

%B J Alzheimers Dis %V 49 %P 1075-83 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26756326?dopt=Abstract %R 10.3233/JAD-150825 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Primary Progressive Aphasia in the Network of French Alzheimer Plan Memory Centers. %A Magnin, Eloi %A Démonet, Jean-François %A Wallon, David %A Dumurgier, Julien %A Troussière, Anne-Cécile %A Jager, Alain %A Duron, Emmanuelle %A Gabelle, Audrey %A de la Sayette, Vincent %A Volpe-Gillot, Lisette %A Tio, Gregory %A Evain, Sarah %A Boutoleau-Bretonnière, Claire %A Enderle, Adeline %A Mouton-Liger, François %A Robert, Philippe %A Hannequin, Didier %A Pasquier, Florence %A Hugon, Jacques %A Paquet, Claire %X

BACKGROUND: Few demographical data about primary progressive aphasia (PPA) are available, and most knowledge regarding PPA is based on tertiary centers' results.

OBJECTIVE: Our aims were to describe demographical characteristics of the PPA population in a large sample of PPA patients from the network of French Alzheimer plan memory centers (Sample 1), and to describe the stratification of cerebrospinal fluid (CSF) biomarkers in two different samples of PPA patients (Samples 2 and 3).

METHODS: All registered PPA patients in the French Alzheimer's disease (AD) databank (Sample 1: n = 2,035) and a subsample (Sample 2: n = 65) derived from a multicentric prospective cohort with CSF biomarker analysis were analyzed. A multicentric retrospective cohort from language expert tertiary centers (Sample 3: n = 97) with CSF biomarker analysis was added. Sample 3 was added to replicate the CSF results of the Sample 2 and to evaluate repartition of AD pathology in the three variant of PPA according to the latest classification.

RESULTS: Non-Fluent/Agrammatic, Logopenic, and Unclassifiable PPA patients (NF/A-Logo-Unclass PPA) were older and more frequent than Semantic PPA patients (2.2 versus 0.8/100,000 inhabitants; p < 0.00001). Male predominance occurred after the age of 80 (p < 0.00001). A higher level of education was observed in the PPA population compared to a typical amnesic AD group. No demographical significant difference between PPA due to AD and not due to AD was observed. The Logopenic variant was most frequent with 85% of AD CSF biomarker profiles (35% in NF/A PPA; 20% in Semantic PPA).

CONCLUSION: PPA occurs also in an elderly population, especially in male patients over 80. CSF biomarkers are useful to stratify PPA. The epidemiology of PPA should be further investigated to confirm gender and cognitive reserve role in PPA to better understand the factors and mechanisms leading to this language-predominant deficit during neurodegenerative diseases.

%B J Alzheimers Dis %V 54 %P 1459-1471 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27589533?dopt=Abstract %R 10.3233/JAD-160536 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Two Phase 2 Multiple Ascending-Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer's Disease. %A Pasquier, Florence %A Sadowsky, Carl %A Holstein, Ann %A Leterme, Ghislaine Le Prince %A Peng, Yahong %A Jackson, Nicholas %A Fox, Nick C %A Ketter, Nzeera %A Liu, Enchi %A Ryan, J Michael %K Adjuvants, Immunologic %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Antipsychotic Agents %K Dose-Response Relationship, Drug %K Female %K Follow-Up Studies %K Humans %K Interferon-gamma %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Recombinant Fusion Proteins %K Saponins %K Single-Blind Method %K Treatment Outcome %X

Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-β (Aβ) plaques in patients with Alzheimer's disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party-unblinded, placebo-controlled, multiple ascending-dose studies of ACC-001 (3μg, 10μg, 30μg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Aβ IgG immunogenicity (secondary objective) up to 12 months after the last vaccination. Exploratory assessments included cognitive/functional measures, brain magnetic resonance imaging (MRI) volumetry, and pharmacodynamic markers in plasma and cerebrospinal fluid (CSF). The most frequent treatment-emergent adverse events (≥10%) were local injection reactions and headache. Amyloid-related imaging abnormalities with vasogenic edema occurred in two (0.8%) patients (ACC-001 30μg + QS-21; ACC-001 10μg). ACC-001 + QS-21 elicited consistently higher peak and sustained anti-Aβ IgG titers compared with ACC-001 alone. Plasma Aβx-40 was significantly higher in all ACC-001 + QS-21 groups versus placebo (weeks 16-56), with no evidence of dose response. Exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers did not show differences or trends between treatment groups and placebo. ACC-001 with or without QS-21 adjuvant has an acceptable safety profile in patients with mild-to-moderate AD.

%B J Alzheimers Dis %V 51 %P 1131-43 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967206?dopt=Abstract %R 10.3233/JAD-150376 %0 Journal Article %J Lancet Neurol %D 2014 %T Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. %A Dubois, Bruno %A Feldman, Howard H %A Jacova, Claudia %A Hampel, Harald %A Molinuevo, José Luis %A Blennow, Kaj %A DeKosky, Steven T %A Gauthier, Serge %A Selkoe, Dennis %A Bateman, Randall %A Cappa, Stefano %A Crutch, Sebastian %A Engelborghs, Sebastiaan %A Frisoni, Giovanni B %A Fox, Nick C %A Galasko, Douglas %A Habert, Marie-Odile %A Jicha, Gregory A %A Nordberg, Agneta %A Pasquier, Florence %A Rabinovici, Gil %A Robert, Philippe %A Rowe, Christopher %A Salloway, Stephen %A Sarazin, Marie %A Epelbaum, Stéphane %A de Souza, Leonardo C %A Vellas, Bruno %A Visser, Pieter J %A Schneider, Lon %A Stern, Yaakov %A Scheltens, Philip %A Cummings, Jeffrey L %K Alzheimer Disease %K Biomarkers %K Humans %K International Cooperation %K Phenotype %K Practice Guidelines as Topic %K Societies, Medical %X

In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.

%B Lancet Neurol %V 13 %P 614-29 %8 2014 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24849862?dopt=Abstract %R 10.1016/S1474-4422(14)70090-0