How many patients are eligible for disease-modifying treatment in Alzheimer's disease? A French national observational study over 5 years.

OBJECTIVE: We aimed to study the epidemiology of the prodromal and mild stages of Alzheimer's disease (AD) patients who are eligible for clinical trials with disease-modifying therapies. SETTINGS: We analysed two large complementary databases to study the incidence and characteristics of this population on a nationwide scope in France from 2014 to 2018. The National Alzheimer Database contains data from 357 memory centres and 90 private neurologists. Data from 2014 to 2018 have been analysed. PARTICIPANTS: Patients, 50-85 years old, diagnosed with AD who had an Mini-Mental State Exam (MMSE) score of ≥20 were included. We excluded patients with mixed and non-AD neurocognitive disorders. PRIMARY OUTCOME MEASURE: Descriptive statistics of the population of interest was the primary measure. RESULTS: In the National Alzheimer Database, 550 198 patients were assessed. Among them, 72 174 (13.1%) were diagnosed with AD and had an MMSE ≥20. Using corrections for specificity of clinical diagnosis of AD, we estimated that about 50 000 (9.1%) had a prodromal or mild AD. In the combined electronic clinical records database of 11 French expert memory centres, a diagnosis of prodromal or mild AD, certified by the use of cerebrospinal fluid AD biomarkers, could be established in 195 (1.3%) out of 14 596 patients. CONCLUSIONS: AD was not frequently diagnosed at a prodromal or mild dementia stage in France in 2014 to 2018. Diagnosis rarely relied on a pathophysiological marker even in expert memory centres. National databases will be valuable to monitor early stage AD diagnosis efficacy in memory centres when a disease-modifying treatment becomes available.

Blood Inflammatory Mediators and Cognitive Decline in Alzheimer's Disease: A Two Years Longitudinal Study.

Peripheral inflammatory processes are involved in Alzheimer's disease (AD). We aimed to determine whether plasma inflammatory mediator levels at diagnosis are associated with cognitive decline through a 2-year follow-up in AD patients. Patients (n = 109, mean age 79.44 (6.82) years) were included at diagnosis with MMSE scores between 16 and 25, with C-reactive protein <10 mg/L, and without any acute or chronic inflammation status. Plasma IL-1ß, IL-6, TNF-α, and CCL5 were measured using Luminex X-MAP technology at baseline, and after one year and two years of follow-up. The mean values of IL-1ß, IL-6, TNF-α, and CCL5 at diagnosis were 0.3, 1.94, 6.57, and 69,615.81 pg/mL, respectively. Mean cognitive decline in MMSE was 3.35 points. No correlation between plasmatic value of IL-1ß, IL-6, TNF-α, or CCL5 at diagnosis and cognitive decline during the two years of follow-up was found. Cognitive decline in AD does not appear to be predictable by the tested inflammatory mediators.

Brain tissue pulsatility mediates cognitive and electrophysiological changes in normal aging: Evidence from ultrasound tissue pulsatility imaging (TPI).

Aging is characterized by a cognitive decline of fluid abilities and is also associated with electrophysiological changes. The vascular hypothesis proposes that brain is sensitive to vascular dysfunction which may accelerate age-related brain modifications and thus explain age-related neurocognitive decline. To test this hypothesis, cognitive performance was measured in 39 healthy participants from 20 to 80 years, using tests assessing inhibition, fluid intelligence, attention and crystallized abilities. Brain functioning associated with attentional abilities was assessed by measuring the P3b ERP component elicited through an auditory oddball paradigm. To assess vascular health, we used an innovative measure of the pulsatility of deep brain tissue, due to variations in cerebral blood flow over the cardiac cycle. Results showed (1) a classical effect of age on fluid neurocognitive measures (inhibition, fluid intelligence, magnitude and latency of the P3b) but not on crystallized measures, (2) that brain pulsatility decreases with advancing age, (3) that brain pulsatility is positively correlated with fluid neurocognitive measures and (4) that brain pulsatility strongly mediated the age-related variance in cognitive performance and the magnitude of the P3b component. The mediating role of the brain pulsatility in age-related effect on neurocognitive measures supports the vascular hypothesis of cognitive aging.

Amyloid PET Positivity in Different Primary Progressive Aphasia Phenotypes.

PURPOSE: Primary progressive aphasia (PPA) is a neurological syndrome in which language functions become progressively impaired with relative sparing of memory and other instrumental functions. The pathologic causes of PPA are heterogeneous, but studies suggest that logopenic PPA (LPA) is underpinned by Alzheimer disease (AD) pathology in a high proportion of cases. The purposes of this descriptive and retrospective study were to characterize F-florbetapir PET imaging in a group of patients with a clinical syndrome of PPA, to determine the value of clinical characterization based on language phenotype in predicting the underlying pathology of PPA with F-florbetapir, and to quantify amyloid load in PPA subjects classified as "positive" F-florbetapir scans. Then, we compare the quantification and distribution of F-florbetapir uptake with those of typical, predominantly amnestic AD patients. METHODS: We conducted a PET study with F-florbetapir in a cohort of 12 right-handed patients diagnosed with PPA: 3 patients with semantic-variant PPA, 5 with nonfluent PPA, 1 with LPA, and 3 unclassifiable patients. We evaluated amyloid deposition between APP groups and 11 patients with typical amnestic AD. RESULTS: Among the 12 patients with PPA syndrome, 8 (66.7%) were considered as amyloid positive. One of the 3 patients with semantic-variant PPA was F-florbetapir positive. In contrast, 4 of the 5 nonfluent-variant PPA, 2 of the 3 unclassifiable cases and the single patient with LPA were F-florbetapir positive. A significantly higher F-florbetapir uptake was observed in PPA F-florbetapir-positive patients compared with typical AD patients. This difference was observed in all regions of interest, except in posterior cingulate and temporal cortex. CONCLUSIONS: These results suggest that F-florbetapir PET may be useful in a routine clinical procedure to improve the reliability of identifying AD pathology in patients with PPA syndrome, with different clinical subtypes of the PPA syndrome.

Hedonic Assessment of Odors: A Comparison of Two Sensory Scales for Use with Alzheimer's Disease Patients and Elderly Individuals.

BACKGROUND: Several clinical studies concerning the olfactory function of patients with cognitive impairment have used sensory scales to investigate hedonic perception. However, no study has focused on the choice of the most appropriate sensory hedonic scale for the individuals with neurodegenerative disorders or other psychiatric diseases involving cognitive deficits. OBJECTIVE: The aim of this study was to investigate the ability of patients with Alzheimer's disease (AD) to use two hedonic scales (category scale and linear scale) and compare their discriminatory capacity, repeatability, and ease of use. This should allow us to identify the most appropriate hedonic scale for patients with AD. METHODS: We recruited 18 patients with mild to moderate AD, and 20 healthy volunteers matched for gender, age, smoking status, and educational level. The participants underwent a clinical assessment and hedonic evaluation of three odorants (pleasant, unpleasant, and neutral), using a five-point category scale and a 10-cm linear scale with a marked mid-point. RESULTS: AD patients were able to use hedonic scales as well as paired healthy elderly subjects. The linear scale performed slightly better in terms of ease of use for both patients and healthy controls and discriminatory capacity for AD patients. The results for AD patients and controls with both scales were repeatable. CONCLUSION: The linear scale may be more appropriate for AD patients pending further studies involving a larger population of patients, using several odorants.

Sleep and mood changes in advanced age after blue-blocking (yellow) intra ocular lens (IOLs) implantation during cataract surgical treatment: a randomized controlled trial.

OBJECTIVES: Both advanced age and depression are characterized by changes in sleep patterns. Light exposure is one of the main synchronizers of circadian cycles and influences sleep by inhibiting melatonin secretion, which is mostly sensitive to light of low wavelengths (blue). Blue-blocking (yellow) intraocular lenses (IOLs) have supplanted the usual UV-blocking (clear) IOLs during cataract surgery to prevent age-related macular degeneration, however, the impact of yellow IOLs on sleep and mood is unclear. The purpose of this study was to compare the effects of yellow and clear IOLs on sleep and mood in aged patients undergoing bilateral cataract surgery. METHODS: A randomized controlled superiority study was conducted within three ophthalmic surgical wards in France. A total of 204 subjects (mean age 76.2 ± 7.5 years) were randomized into yellow or clear IOLs groups. Patients completed a sleep diary, the pictorial sleepiness scale and the Beck Depression Inventory (BDI) one week before and eight weeks after the last surgical procedure. RESULTS: According to an Intent To Treat (ITT) analysis, no significant difference was found between yellow and clear IOLs groups regarding sleep time, sleep latency, total sleep duration, quality of sleep and BDI scores. The rate of patients whose BDI score increased at the cutoff score of ≥5 after surgery was significantly higher in the yellow IOL group (n = 11, 13.1%) compared with the clear IOL group (n = 4; 4.7%); p = 0.02. CONCLUSIONS: Using yellow IOLs for cataract surgery doesn't significantly impact sleep but may induce mood changes in aging.

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

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 18F-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.

Fluoxetine induces paradoxical effects in C57BL6/J mice: comparison with BALB/c mice.

The C57BL6/J mouse is the most commonly used strain in genetic investigations and behavioural tests. However, only a few studies have used C57BL6/J mice to assess the effects of antidepressant compounds. We carried out a study to compare the behavioural effects of fluoxetine (FLX) in a model of depression in two mice strains: C57BL6/J and BALB/c. We used an 8-week unpredictable chronic mild stress (UCMS) protocol during which FLX was administered (15 mg/kg, oral) from the third week to the end of the protocol. We found that UCMS induced degradation of the coat state in the two strains. Moreover, as expected, we observed that FLX elicited antidepressant-like effects in the BALB/c mice by reducing the coat state deterioration and the latency of grooming in splash test. However, in the C57BL6/J mice, it did not induce this action, but instead triggered an opposite effect: an increased sniffing latency in the novelty suppression of feeding test. We conclude that FLX exerts a paradoxical effect in the C57Bl6/J strain. This observation is consistent with some clinical features of hyper-reactivity to FLX observed in humans. Therefore, the UCMS protocol used in C57Bl6/J mice could be a good model to study the mechanisms of the paradoxical effects caused by selective serotonin reuptake inhibitors.

Audiometric evaluation in patients with Alzheimer's disease.

The objective of this study is to assess the validity of ASSR as a complementary diagnostic test for peripheral hearing loss by proving a significant correlation between behavioral thresholds and ASSR. The design used in this study is monocentric prospective study from November 2014 to April 2015. The setting used in this study is the ENT-Head and Neck Surgery Department and Geriatrics Department in a French Regional and University Hospital. The participants are patients over 75 years with cognitive impairment (Alzheimer's disease or mild-cognitive impairment) with a Mini-Mental State Examination score under 27/30 and without hearing aids. Exclusion criteria were: otoscopic and middle ear abnormalities, retro-cochlear lesion, other types of dementia, and central nervous system disease altering cerebral lateralization. The intervention used in this study is pure-tone audiometry, speech audiometry, dichotic listening test, and auditory steady-state responses recording. The correlations between these exams were studied with Pearson's correlation coefficient and Student's t test. Results were significant if p < 0.05. Twenty-three ears were analyzed from 12 patients. There were six women and six men with cognitive impairment, mean age 82.1 (±4.6) years, and mean MMSE score that was 21.3/30 (±5.7). The correlation between pure-tone audiometry and ASSR was significant for all frequencies: r = 0.55 (p = 0.006) for 500 Hz, r = 0.58 (p = 0.005) for 1000 Hz, r = 0.61 (p = 0.003) for 2000 Hz, and r = 0.66 (p = 0.002) for 4000 Hz. There was no significant correlation between the MMSE and the difference between ASSR and PTA on each frequency. The dichotic listening test showed a right ear advantage (50.9 %, p = 0.039). The ASSR in patients with cognitive impairment and understanding troubles is a promising complementary technique to estimate the hearing thresholds.

Symptomatic treatments in Alzheimer's disease in 2016: a study from Memory centers in France.

Cholinesterase inhibitors and memantine are used from 15 years, in Alzheimer's disease. Benefits have been demonstrated according to cognition, activities of daily living, affective symptoms and behavior, and global impression of change. The aims of this paper are: 1) to describe how these treatments are used in France with a sample survey managed by the national federation of the french CMRR; 2) to study data about efficacy, safety, medicoeconomic impacts and how they are used in Europe.

Pharmacological treatments of behavioral and psychological symptoms of dementia in Alzheimer's disease: role of acetylcholinesterase inhibitors and memantine.

Behavioral and psychological symptoms of dementia (BPSD) are frequent in Alzheimer's disease (AD). They are associated with disability and suffering for both the patients and their caregivers. Even if BPSD are now well diagnosed and characterized by standardized tools, their treatment remains often challenging in clinical setting because of the frequent and severe side effects of the psychotropic drugs when used in this indication. Evidence-based data confirm that antipsychotics and antidepressants are efficient for the treatment of BPSD but have a poor tolerance profile and their use is problematic. Use of cholinesterase inhibitors and memantine, whom French authorities have questioned the relevance in 2008, also have a significant efficacy on non-cognitive symptoms of AD. Therefore, and although their tolerance profile is considered unsatisfying, they keep an indication in patients with AD and BPSD.

Limiting Factors of Brain Donation in Neurodegenerative Diseases: The Example of French Memory Clinics.

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.

Quality of Life After Off-Label Thrombolysis for Ischemic Stroke in Elderly Patients.

INTRODUCTION: The use of intravenous thrombolysis with alteplase for ischemic stroke in Europe is restricted to subjects aged <80 years. Recent studies have reported the efficacy and safety of alteplase in older patients. However, data concerning the quality of life (QOL) of these elderly subjects are sparse. OBJECTIVES: The aim of this study was to compare the QOL of patients aged ≥80 years with that of patients aged <80 years at 3 months after thrombolysis. METHOD: This was a prospective study comprising French-speaking patients aged >18 years treated using thrombolytic therapy for ischemic stroke at the Hospital of Tours (Tours, France) between June 2012 and January 2013. QOL was assessed using the Stroke Impact Scale (SIS). The presence of mood disorders or cognitive impairments was also assessed. RESULTS: QOL was evaluated for 62 subjects among the 83 enrolled patients who received thrombolytic treatment; 21 patients were aged >80 years. Concerning scores on the SIS, using a multivariate analysis, only the memory and thinking score was significantly and negatively associated with the elderly population [odds ratio (OR) 0.036, 95% confidence interval (CI) 0.004-0.339; p = 0.004]. No significant difference was observed among all the other QOL scores. Neurological recovery and functional status did not differ between the two groups. CONCLUSION: QOL after intravenous thrombolysis in the elderly population was comparable to that of younger subjects. Despite its small sample size, this study showed promising results in favor of intravenous thrombolysis in the elderly population and highlighted the importance of systematic screening for post-stroke cognitive impairment, particularly in this population.

Precuneus and Cingulate Cortex Atrophy and Hypometabolism in Patients with Alzheimer's Disease and Mild Cognitive Impairment: MRI and (18)F-FDG PET Quantitative Analysis Using FreeSurfer.

OBJECTIVE: The objective of this study was to compare glucose metabolism and atrophy, in the precuneus and cingulate cortex, in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI), using FreeSurfer. METHODS: 47 individuals (17 patients with AD, 17 patients with amnestic MCI, and 13 healthy controls (HC)) were included. MRI and PET images using (18)F-FDG (mean injected dose of 185 MBq) were acquired and analyzed using FreeSurfer to define regions of interest in the hippocampus, amygdala, precuneus, and anterior and posterior cingulate cortex. Regional volumes were generated. PET images were registered to the T1-weighted MRI images and regional uptake normalized by cerebellum uptake (SUVr) was measured. RESULTS: Mean posterior cingulate volume was reduced in MCI and AD. SUVr were different between the three groups: mean precuneus SUVr was 1.02 for AD, 1.09 for MCI, and 1.26 for controls (p < 0.05); mean posterior cingulate SUVr was 0.96, 1.06, and 1.22 for AD, MCI, and controls, respectively (p < 0.05). CONCLUSION: We found graduated hypometabolism in the posterior cingulate cortex and the precuneus in prodromal AD (MCI) and AD, whereas atrophy was not significant. This suggests that the use of (18)F-FDG in these two regions could be a neurodegenerative biomarker.

[Hearing loss and Alzheimer's disease]. / Déficit auditif et maladie d'Alzheimer.

Recent studies suggest that subjects with hearing loss are more likely to develop Alzheimer's disease. Hearing loss can be consecutive to presbycusis and/or to central auditory dysfunction. Standard audiometric measures (pure tone and speech intelligibility) allow the diagnosis of presbycusis. However, to demonstrate central auditory dysfunction, specific audiometric tests are needed such as noisy and/or dichotic tests. Actually, no consensus exists to investigate hearing loss in people with Alzheimer's disease though hearing loss may be an early manifestation of Alzheimer's disease. Until now, investigations and clinical procedure related to the diagnosis of Alzheimer's disease ignored the hearing ability of the patient. However, the major part of care management and investigations implies the patient's communication ability with the caregivers. Hearing loss may be one of the most unrecognized deficit in subjects with Alzheimer's disease. Auditory rehabilitation could benefit to the patient in order to lessen cognitive decline, but this must be investigated during longitudinal studies in order to clearly demonstrate their efficiency.

Taste identification used as a potential discriminative test among depression and Alzheimer׳s disease in elderly: A pilot study.

Major Depression and Alzheimer׳s disease (AD) are two diseases in the elderly characterized by an overlap of early symptoms including memory and emotional disorders. The identification of specific markers would facilitate their diagnosis. The aim of this study was to identify such markers by investigating gustatory function in depressed and AD patients. We included 20 patients with unipolar major depressive episodes (MDE), 20 patients with mild to moderate AD and 24 healthy individuals. We investigated the cognitive profile (depression, global cognitive efficiency and social/physical anhedonia) and gustatory function (ability to identify four basic tastes and to judge their intensity and hedonic value) in all participants. We found that AD patients performed worse than healthy participants in the taste identification test (for the analysis of all tastants together); however, this was not the case for depressed patients. We found no significant differences among the three groups in their ability to evaluate the intensity and hedonic value of the four tastes. Overall, our findings suggest that a taste identification test may be useful to distinguish AD and healthy controls but further investigation is required to conclude whether such a test can differentiate AD and depressed patients.

Association between comorbidity burden and rapid cognitive decline in individuals with mild to moderate Alzheimer's disease.

OBJECTIVES: To determine the association between rapid cognitive decline and burden of comorbidities as assessed using the Charlson Comorbidity Index in individuals aged 65 and older with Alzheimer's disease (AD). DESIGN: Retrospective cohort study. SETTING: Memory clinic at the University Hospital of Nantes. PARTICIPANTS: Individuals aged 65 and older with AD (n=170). MEASUREMENTS: Subjects were followed for 1 year. Rapid cognitive decline was defined as a decrease of 3 or more points on the Mini-Mental State Examination per 12-month period. Variables studied were the Charlson Comorbidity Index (measure of comorbidity burden), age, sex, AD stage, type of residence (living at home or not), presence of caregiver, functional abilities (Lawton and Katz scales), risk of malnutrition or depression, and intercurrent events (hospitalization or initiating home care). RESULTS: Rapid cognitive decline at 1-year follow-up occurred in 65 subjects (38.2%). In fully adjusted logistic regression analysis, Charlson Comorbidity Index was significantly associated with rapid cognitive decline (odds ratio (OR)=1.30, P=.03). Moderate stage of AD (OR=2.07, P=.04) and living at home (OR=4.17, P=.04) were also associated with rapid cognitive decline. CONCLUSION: Comorbidity burden was associated with rapid cognitive decline in subjects with AD.