The pattern of cortical thickness associated with executive dysfunction in MCI and SCC: The MEMENTO cohort.

BACKGROUND: The association between the pattern of cortical thickness (CT) and executive dysfunction (ED) in mild cognitive impairment (MCI) and subjective cognitive complaints (SCC) is still poorly understood. We aimed to investigate the association between CT and ED in a large French cohort (MEMENTO) of 2323 participants with MCI or SCC. METHODS: All participants with available CT and executive function data (verbal fluency and Trail Making Test [TMT]) were selected (n=1924). Linear regressions were performed to determine relationships between executive performance and the brain parenchymal fraction (BPF) and CT using FreeSurfer. RESULTS: The global executive function score was related to the BPF (sß: 0.091, P<0.001) and CT in the right supramarginal (sß: 0.060, P=0.041) and right isthmus cingulate (sß: 0.062, P=0.011) regions. Literal verbal fluency was related to the BPF (sß: 0.125, P<0.001) and CT in the left parsorbitalis region (sß: 0.045, P=0.045). Semantic verbal fluency was related to the BPF (sß: 0.101, P<0.001) and CT in the right supramarginal region (sß: 0.061, P=0.042). The time difference between the TMT parts B and A was related to the BPF (sß: 0.048, P=0.045) and CT in the right precuneus (sß: 0.073, P=0.019) and right isthmus cingulate region (sß: 0.054, P=0.032). CONCLUSIONS: In a large clinically based cohort of participants presenting with either MCI or SCC (a potential early stage of Alzheimer's disease [AD]), ED was related to the BPF and CT in the left pars orbitalis, right precuneus, right supramarginal, and right isthmus cingulate regions. This pattern of lesions adds knowledge to the conventional anatomy of ED and could contribute to the early diagnosis of AD.

The free plasma amyloid Aß1-42/Aß1-40 ratio predicts conversion to dementia for subjects with mild cognitive impairment with performance equivalent to that of the total plasma Aß1-42/Aß1-40 ratio. The BALTAZAR study.

BACKGROUND AND PURPOSE: Blood-based biomarkers are a non-invasive solution to predict the risk of conversion of mild cognitive impairment (MCI) to dementia. The utility of free plasma amyloid peptides (not bound to plasma proteins and/or cells) as an early indicator of conversion to dementia is still debated, as the results of studies have been contradictory. In this context, we investigated whether plasma levels of the free amyloid peptides Aß1-42 and Aß1-40 and the free plasma Aß1-42/Aß1-40 ratio are associated with the conversion of MCI to dementia, in particular AD, over three years of follow-up in a subgroup of the BALTAZAR cohort. We also compared their predictive value to that of total plasma Aß1-42 and Aß1-40 levels and the total plasma Aß1-42/Aß1-40 ratio. METHODS: The plasma Aß1-42 and Aß1-40 peptide assay was performed using the INNO-BIA kit (Fujirebio Europe). Free amyloid levels (defined by the amyloid fraction directly accessible to antibodies of the assay) were obtained with the undiluted plasma, whereas total amyloid levels were obtained after the dilution of plasma (1/3) with a denaturing buffer. Free and total Aß1-42 and Aß1-40 levels were measured at inclusion for a subgroup of participants (N = 106) with mild cognitive impairment (MCI) from the BALTAZAR study (a large-scale longitudinal multicenter cohort with a three-year follow-up). Associations between conversion and the free/total plasma Aß1-42 and Aß1-40 levels and Aß1-42/Aß1-40 ratio were analyzed using logistic and Cox Proportional Hazards models. Demographic, clinical, cognitive (MMSE, ADL and IADL), APOE, and MRI characteristics (relative hippocampal volume) were compared using non-parametric (Mann-Whitney) or parametric (Student) tests for quantitative variables and Chi-square or Fisher exact tests for qualitative variables. RESULTS: The risk of conversion to dementia was lower for patients in the highest quartile of free plasma Aß1-42/Aß1-40 (≥ 25.8%) than those in the three lower quartiles: hazard ratio = 0.36 (95% confidence interval [0.15-0.87]), after adjustment for age, sex, education, and APOE ε4 (p-value = 0.022). This was comparable to the risk of conversion in the highest quartile of total plasma Aß1-42/Aß1-40: hazard ratio = 0.37 (95% confidence interval [0.16-0.89], p-value = 0.027). However, while patients in the highest quartile of total plasma Aß1-42/Aß1-40 showed higher MMSE scores and a higher hippocampal volume than patients in the three lowest quartiles of total plasma Aß1-42/Aß1-40, as well as normal CSF biomarker levels, the patients in the highest quartile of free plasma Aß1-42/Aß1-40 did not show any significant differences in MMSE scores, hippocampal volume, or CSF biomarker levels relative to the three lowest quartiles of free plasma Aß1-42/Aß1-40. CONCLUSION: The free plasma Aß1-42/Aß1-40 ratio is associated with a risk of conversion from MCI to dementia within three years, with performance comparable to that of the total plasma Aß1-42/Aß1-40 ratio. Threshold levels of the free and total plasma Aß1-42/Aß1-40 ratio could be determined, with a 60% lower risk of conversion for patients above the threshold than those below.

Forecasting the Prevalence of Alzheimer's Disease at Mild Cognitive Impairment and Mild Dementia Stages in France in 2022.

BACKGROUND: Given the evolution of early diagnosis guidelines and future disease-modifying therapies, estimating the prevalence of Alzheimer's disease (AD) at early stages is key. OBJECTIVE: To estimate the number of people living with mild cognitive impairment (MCI) due to AD and mild AD dementia in France in 2022 that could be eligible to future AD therapies. METHODS: A step-by-step approach was defined based on disease stages definition and clinical practice. In line with AD guidelines, amyloid-positive profile is considered in our estimates to enhance the diagnosis accuracy of early stages of AD. Age-stratified prevalence from French cohort and international pooled analyses were identified to feed the different steps. To consider uncertainty around mean prevalence values, low and high scenarii based on the lower and upper bounds of the 95% confidence interval were conducted. RESULTS: We estimated that 2.5 (low scenario: 1.7 - high scenario: 3.6) million people suffer from mild cognitive impairment in France in 2022 among whom 1.65 (low: 1.5 - high: 1.8) million people meet the criteria for mild cognitive impairment due to AD i.e., with amyloid positive profile. The expected number of clinical AD dementia is estimated at 925,886 people. Among those, 379,278 people suffer from mild AD dementia based on clinical diagnosis, including 311,043 (low: 289,174 - high: 328,332) cases with amyloid positive profile. CONCLUSION: MCI due to AD, and mild dementia stages are potentially of high prevalence. Population-based studies are needed to confirm those estimates.

Diagnosis associated with Tau higher than 1200 pg/mL: Insights from the clinical and laboratory practice.

CONTEXT: Cerebrospinal fluid (CSF) biomarkers are valuable tools for the diagnosis of neurological diseases. We aimed to investigate within a retrospective multicentric study the final diagnosis associated with very high CSF Tau levels and to identify patterns of biomarkers that would differentiate them in clinical practice, to help clinical biologists into physicians' counseling. PATIENTS AND METHODS: Within the national multicentric network ePLM, we included 1743 patients from January 1, 2008, to December 31, 2013, with CSF biomarkers assayed by the same Innotest assays (protein Tau, phospho-Tau [pTau], and Aß 1-42). We identified 205 patients with protein Tau concentration higher than 1200 pg/mL and final diagnosis. RESULTS: Among those patients, 105 (51.2%) were suffering from Alzheimer's disease, 37 (18%) from sporadic Creuztfeldt-Jakob disease, and 63 (30.7%) from other neurological diseases including paraneoplastic/ central nervous system tumor, frontotemporal dementia, other diagnoses, amyloid angiopathy, Lewy body dementia, and infections of the central nervous system. Phospho-Tau, Aß1-42 and Aß1-42/pTau values differed significantly between the three groups of patients (p < .001). An Aß1-42/pTau ratio between 4.7 and 9.7 was suggestive of other neurological diseases (threshold in AD: 8.3). CSF 14-3-3 was useful to discriminate Alzheimer's disease from Creuztfeldt-Jakob disease in case of Aß1-42 concentrations <550 pg/mL or pTau>60 pg/mL. CONCLUSION: This work emphasizes the interest of a well-thought-out interpretation of CSF biomarkers in neurological diseases, particularly in the case of high Tau protein concentrations in the CSF.

Generation of induced pluripotent stem cells (iPSCs) IRMBi002-A from an Alzheimer's disease patient carrying a D694N mutation in the APP gene.

Induced pluripotent stem cells (iPSC) were generated from skin fibroblasts obtained from a 58 year-old woman suffering from Alzheimer's disease and carrying a D694N mutation on Amyloid precursor protein (APP). Fibroblasts were reprogrammed into iPSC using the integration-free Sendai Virus which allows the expression of the Yamanaka factors. Verification of their pluripotency was achieved by demonstrating the expression of pluripotency markers and their differentiation potential into the three primary germ layers. The cells have the corresponding mutation and present a normal karyotype. The reported APP-D694N iPSC line may be used to model and study human AD pathology in vitro.

Generation of induced pluripotent stem cells (IRMBi001-A) from an Alzheimer's disease patient carrying a G217D mutation in the PSEN1 gene.

Induced pluripotent stem cells (iPSC) were generated from skin fibroblasts obtained from a 50 year-old patient suffering from Alzheimer's disease and carrying a G217D causal mutation on presenilin 1 (PSEN1). iPSCs were obtained following reprogramming using the integration-free Sendai Virus system which allows expression of the Yamanaka factors. Verification of their pluripotency was achieved by demonstrating the expression of pluripotency markers and their differentiation potential into the three primary germ layers. iPS cells carry the patient G217D mutation and present a normal karyotype. The reported PS1-G217D iPSC line may be used to model and study human AD pathology in vitro.

[Alzheimer's disease cerebro-spinal fluid biomarkers: A clinical research tool sometimes useful in daily clinical practice of memory clinics for the diagnosis of complex cases]. / Les biomarqueurs du liquide cérébro-spinal dans la maladie d'Alzheimer : un outil de recherche utile dans la pratique clinique courante des consultations mémoire pour les cas complexes.

The role of biomarkers in clinical research was recently highlighted in the new criteria for the diagnosis of Alzheimer's disease. Cerebro-spinal fluid (CSF) biomarkers (total Tau protein, threonine 181 phosphorylated Tau protein and amyloid Aß1-42 peptide) are associated with cerebral neuropathological lesions observed in Alzheimer's disease (neuronal death, neurofibrillary tangle with abnormal Tau deposits and amyloid plaque). Aß1-40 amyloid peptide dosage helps to interpret Aß1-42 results. As suggested in the latest international criteria and the French HAS (Haute Autorité de santé) recommendations, using theses CSF biomarkers should not be systematic but sometimes could be performed to improve confidence about the diagnostic of Alzheimer's disease in young subjects or in complex clinical situations. Future biomarkers actually in development will additionally help in diagnostic process (differential diagnosis) and in prognostic evaluation of neurodegenerative diseases.

Are migraine and non-migrainous headache risk factors for stroke in the elderly? Findings from a 12-year cohort follow-up.

BACKGROUND AND PURPOSE: There is evidence that migraine is a risk factor for stroke but little is known about this association in elderly people. Furthermore, non-migrainous headache (NMH) has received little attention despite being the most frequently reported type of headache. Late-life migraine and NMH were examined as candidate risk factors for stroke in a community-dwelling elderly sample over a 12-year follow-up. METHODS: One thousand nine hundred and nineteen non-institutionalized subjects aged 65+, without dementia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, DSM-IV criteria) and with no stroke history at baseline, were drawn from the Three-City Montpellier cohort (recruitment 1999-2001) for longitudinal analysis. Ischaemic and haemorrhagic stroke was reported at baseline and at each of the five follow-ups, with cases validated by a panel of experts, according to ICD-10 criteria (International Classification of Diseases, 10th revision). Migraine and NMH were determined at baseline during a neurological interview and examination using 1988 International Headache Society criteria. RESULTS: A total of 110 (5.4%) cases of migraine and 179 (8.9%) cases of NMH were identified at baseline. During the median 8.8-year follow-up, incident stroke was observed in 1.9% of baseline migrainers, 6.2% of NMH and 3.6% of those with no lifetime history of headache. Cox proportional hazard models indicated that migraine was not a risk factor for stroke; however, NMH sufferers were twice as likely to have a stroke (hazard ratio 2.00, 95% confidence interval 1.00-3.93, P = 0.049). CONCLUSIONS: This study is one of the first to suggest that late-life NMH rather than migraine could be an independent risk factor for stroke and a warning sign. The incidence of stroke in elderly migrainers, seldom reported, is particularly low.

How to optimize the use of biobanks from population-based cohorts in aging research.

In epidemiological cohorts, there is an increased interest for the implementation of biobanks. The potential role of biological determinants of diseases needs to be investigated before the onset of the event of interest in order to limit the problems encountered when examining biological determinants in classical case-control studies. Biobank is now a very sophisticated system that consists of a programmed storage of biological material and related data. Our aim in this paper is to document how biobank constitution is useful for studying biological determinants of aging and to give some indications on methodological issues that can be helpful to optimize the constitution and use of biobanks in aging cohorts. Optimization of sampling through two-phase designs (nested case control or case-cohort studies) allows better efficiency. These elements are, for most of them, not specific to aging populations but are useful more generally for the epidemiology of chronic diseases. Our purpose will be illustrated with some examples and results obtained in an ongoing aging cohort, the Three-City Study.

[Injectable preparation of labeled leucine with the carbon 13 for a clinical research program on the Alzheimer disease: pharmaceutical control of raw materials and the finished product and stability study]. / Préparation injectable de leucine marquée au carbone 13 pour un programme de recherche clinique sur la maladie d'Alzheimer : contrôle pharmaceutique des matières premières et du produit fini et étude de stabilité

INTRODUCTION: The L-leucine labeled (L-[U-(13)C] Leu) is a stable isotopic tracer administered by parenteral route within the framework of a new clinical research program concerning the diagnosis of the Alzheimer's disease. To meet regulatory requirements and have ready to use solution with an expiration date, a pharmaceutical control of raw materials and the finished product followed by a stability study were realised. MATERIALS AND METHOD: After the pharmaceutical control of raw materials, the solution of L-[U-(13)C] Leu was prepared according to the good practices preparation. Prepared bottles were stored for 1 year of a share in a climatic chamber (25 °C±2 °C) and the other in a refrigerator (5 °C±3 °C). To assess stability, the physicochemical controls (pH, osmolality, sub-visible particles, L-[U-(13)C] Leu concentration, sodium concentration, isotopic enrichment) and microbiological (bacterial endotoxin and sterility) were performed at regular intervals for 1 year. RESULTS: Neither significant decrease of L-[U-(13)C] Leu concentration and sodium concentration nor pH and osmolality variation were observed for 1 year. Isotopic enrichment higher than 99.9% reflected the stability of labelling of L-leucine molecule. The sub-visible particles, the bacterial endotoxin and sterility were in accordance with the European pharmacopoeia attesting limpidity, apyrogenicity and sterility of this injectable preparation. DISCUSSION AND CONCLUSION: The injectable preparation of L-[U-(13)C] Leu was stable after 1 year for two preservation conditions, ensuring to safety for administration for human within the framework of this clinical research.

Amyloid imaging in Alzheimer's disease: a literature review.

Therapies targeting amyloid-ß peptide currently represent approximately 50% of drugs now being developed for Alzheimer's disease. Some, including active and passive anti-Aß immunotherapy, directly target the amyloid plaques. The new amyloid tracers are increasingly being included in the proposed updated diagnostic criteria, and may allow earlier diagnosis. Those targeting amyloid-ß peptide allow identification of amyloid plaques in vivo. We need to gain insight into all aspects of their application. As florbetapir (Amyvid™) and flutemetamol (Vizamyl™) have received marketing authorization, clinicians require deeper knowledge to be rationally used in diagnosis. In this paper, we review both completed and ongoing observational, longitudinal and interventional studies of these tracers, our main objective being to show the performance of the four most commonly used tracers and their validation.

Biomarkers of Alzheimer's disease: the present and the future.

A paradigm shift has occurred in the last ten years in the diagnostic field of Alzheimer's disease (AD). Scientific thought has enriched the concept of AD as a pathophysiological continuum and emphasized contribution of biological, morphological and functional brain imaging biomarkers for diagnosis, in particular during the early stages of the disease. We address here the present and the future of these biological biomarkers. Most of them are linked to the pathophysiological lesions of the Alzheimer process: aggregates of hyperphosphorylated tau proteins, also called neurofibrillary tangles (NFT), and extracellular deposit of amyloid-beta peptides (Aß), also called senile plaques. The detection in the cerebrospinal fluid (CSF) of tau and Aß represents the current diagnostic practice of AD. Improvement for a more accurate and earlier biological diagnosis is however expected using a new generation of biomarkers, mostly in relation with tau and Aß metabolism.

Neurodegenerative dementia and parkinsonism.

BACKGROUND: Dementia and Parkinsonism are two major neurodegenerative disorders. Accurate diagnosis can be difficult when patients have both syndromes because of a wide range of etiologies. OBJECTIVES: To improve clinical diagnosis, we propose a disease classification based on the pathological proteins which are involved in the neuropathological disease process. DESIGN: Four neuropathological classes are proposed based on four major proteins, tau, A beta, alpha -synuclein and TDP43 : 1/ Tauopathy and amyloidopathy with possible Parkinsonism, 2/ Tauopathy with predominant Parkinsonism, 3/ Synucleinopathies with cognitive impairment/dementia and 4/ The TAR DNA binding protein 43 (TDP-43). This classification raises certain questions in clinical practice due to intriguing overlaps between clinical presentations despite the same pathological protein being involved. CONCLUSION: The development of molecular and pathological protein research in neurodegenerative disorders can help classify the clinical association of dementia and Parkinsonism and improve therapeutic strategies against proteins involved in the degenerative process.

Gene and cell therapy for prion diseases.

Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal prion protein named PrP(Sc). PrP(Sc) results from the post-translational conformational modification of the host-encoded protein PrP(C). To date there is no treatment for this inexorably fatal disease. Hence, a major focus of research consists in the identification of new molecules that could interfere with in vivo prion propagation. Promising therapeutic approaches to block the production of PrP(Sc) are based on PrP RNA interference, passive or active immunization, dominant negative inhibition of PrP(Sc) formation, as well as inhibition of interactions between PrP(Sc) and other cofactors. Although these anti-prion molecules can be directly administered in vivo, the process to produce and purify them in high quantity is often challenging and expensive. An alternative strategy consists in the development of gene therapy systems of delivery. Importantly, the diagnosis of prion disease in humans remains difficult and often leaves a short therapeutic window after the appearance of the first clinical signs. As serious damages to the brain generally occur before clinical symptoms manifest, an ideal therapeutic strategy must target not only the formation of toxic aggregates, but also the brain destruction already incurred. This could be achieved by combining gene therapy with cell therapy. In this review we have chosen to highlight the multiple targets and potential gene or cell replacement therapeutic approaches. This review also presents the evidence for the transplantation of stem cells as well as the combination of cell and gene therapy as promising strategies against prion diseases.

[CSF biomarkers: proteomics investigations and clinical applications in neurodegenerative disorders]. / Les marqueurs biologiques protéiques du liquide céphalorachidien: caractéristiques et implications cliniques dans les démences.

Given the current developments of therapeutic strategies in the field of neurodegenerative disorders, exact diagnosis, especially at an early stage, is becoming increasingly crucial for optimal patient care. Importantly, the new diagnosis criteria of dementia include functional imagery as well as CSF biomarkers. Proteomics investigations of these CSF biomarkers have produced quite promising results. The interest of CSF analysis resides in the anatomical and pathophysiological characteristics of this fluid. In this article, we will review current proteomics investigations of CSF which have led to the discovery and validation of biomarkers, mainly in the field of neurodegenerative disorders in Alzheimer's disease.

[Sensory-motor neuropathy: a slow and misleading case of leprosy]. / Neuropathie périphérique sensitivomotrice : une forme lente et trompeuse de maladie de Hansen.

The diagnostic process of sensory-motor neuropathies is difficult. Atypical variants and rare etiologies also contribute to delay the diagnosis. We report the case of a 70-year-old woman with slowly progressive asymmetric axonal sensory-motor neuropathy. Leprosy was identified after an eight-year delay. Nerve biopsy was required to establish the diagnosis: electron microscopy revealed debris of Hansen's bacillus in the nerve. Treatment was fully curative after several months. Leprosy is a rare cause of neuropathy in Europeans. Systematic inquiry about travel to endemic areas would be helpful in establishing the diagnosis. In such cases, nerve biopsy is crucial.

[Leflunomide-related severe axonal neuropathy]. / Neuropathie axonale sévère et léflunomide.

INTRODUCTION: Leflunomide is a new drug for the treatment of rheumatoid arthritis. Its mechanism of action is based on lymphocyte inhibition. We report the cases of two patients treated with leflunomide who developed severe sensory-motor axonal polyneuropathy. OBSERVATION: Two women (61- and 70-year-old) presented with a sensory-motor axonal polyneuropathy beginning 5 months after onset of leflunomide treatment. Etiologic investigations were negative. The symptoms rapidly improved after withdrawing leflunomide. DISCUSSION: The analysis of drug watch data found twelve patients with leflunomide-related neuropathy. Ten of them were more than 60 years old. The mean delay for onset of neuropathy was 9 months. The neuropathy improved after treatment withdrawal in seven patients. CONCLUSION: We consider these data strongly suggest that leflunomide is a cause of axonal sensory-motor neuropathy. The prevalence of such adverse events is still unknown.