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Background Brain amyloid deposition and neurofibrillary tangles in Alzheimer’s disease (AD) are associated with complex neuroinflammatory reactions such as microglial activation and cytokine production. Glucose metabolism is closely related to neuroinflammation. Ketogenic diets (KDs) include a high amount of fat, low carbohydrate and medium-chain triglyceride (MCT) intake. KDs lead to the production of ketone bodies to fuel the brain, in the absence of glucose. These nutritional interventions are validated treatments of pharmacoresistant epilepsy, consequently leading to a better intellectual development in epileptic children. In neurodegenerative diseases and cognitive decline, potential benefits of KD were previously pointed out, but the published evidence remains scarce. The main objective of this review was to critically examine the evidence regarding KD or MCT intake effects both in AD and ageing animal models and in humans. Main body We conducted a review based on a systematic search of interventional trials published from January 2000 to March 2019 found on MEDLINE and Cochrane databases. Overall, 11 animal and 11 human studies were included in the present review. In preclinical studies, this review revealed an improvement of cognition and motor function in AD mouse model and ageing animals. However, the KD and ketone supplementation were also associated with significant weight loss. In human studies, most of the published articles showed a significant improvement of cognitive outcomes (global cognition, memory and executive functions) with ketone supplementation or KD, regardless of the severity of cognitive impairments previously detected. Both interventions seemed acceptable and efficient to achieve ketosis. Conclusion The KD or MCT intake might be promising ways to alter cognitive symptoms in AD, especially at the prodromal stage of the disease. The need for efficient disease-modifying strategies suggests to pursue further KD interventional studies to assess the efficacy, the adherence to this diet and the potential adverse effects of these nutritional approaches.

Background Analysis of selected research cohorts has highlighted an association between plasma neurofilament light (NfL) protein and cross-sectional cognitive impairment as well as longitudinal cognitive decline. However, the findings have yielded inconsistent results regarding its possible application in clinical practice. Despite its potential prognostic significance, the role of plasma NfL in daily clinical practice with unselected patients suffering from cognitive impairment remains largely unexplored. Methods This retrospective, cross-sectional and longitudinal monocentric study enrolled 320 patients with Alzheimer’s disease ([AD], n  = 158), dementia with Lewy body ([DLB], n  = 30), frontotemporal dementia ([FTD], n  = 32), non-neurodegenerative diseases ([NND], n  = 59) or subjective cognitive decline ([SCD], n  = 41). Plasma NfL levels were measured at baseline on the Simoa platform. AD, DLB, and FTD patients were also analyzed altogether as a ‘degenerative conditions’ subgroup, whereas SCD and NND were grouped as a ‘non-degenerative conditions’ subgroup. We assessed the relationship between plasma NfL levels and cross-sectional cognitive performance, including global cognition and six specific cognitive domains. A subset of 239 patients had follow-up mini-mental state examinations (MMSE) up to 60 months. Models were adjusted on age, education level, glomerular filtration rate and body mass index. Results In 320 patients, baseline plasma NfL levels were negatively associated with global cognition (β=-1.28 (-1.81 ; -0.75) P  < 0.001), memory (β=-1.48 (-2.38 ; -0.59), P  = 0.001), language (β=-1.72(-2.49 ; -0.95) P  < 0.001), praxis (β=-2.02 (-2.91 ; -1.13) P  < 0.001) and executive functions (β=-0.81, P  < 0.001). Across diagnosis, plasma NfL levels were negatively associated with cross-sectional global cognition in all but the SCD subgroup, specifically with executive functions and memory in AD (respectively β=-0.71(-1.21 ; -0.211), P  = 0.005 and β=-1.29 (-2.17 ; -0.42), P  = 0.004), and with attention in LBD (β=-0.81(-1.16 ; -0.002), P  = 0.03). Linear mixed-effects models showed that plasma NfL predicted MMSE decline in the global population (β PlasmaNfLxTime =-0.15 (-0.26 ; -0.04), P  = 0.006), as in the neurodegenerative condition subgroup (β PlasmaNfLxTime =-0.21 (-0.37 ; − 0.06), P  = 0.007), but not in non-neurodegenerative condition subgroup. Conclusion In our clinical cohort, plasma NfL was associated with faster cognitive decline in neurodegenerative dementia, which corroborates data obtained in research cohorts. Yet, plasma NfL was not predictive of accelerated cognitive decline in individuals without neurodegeneration, suggesting its use as a neurodegeneration-specific predictive biomarker.

To assess the validity of the Mini Nutritional Assessment-Short Form (MNA-SF) in elderly patients from the Toulouse Frailty Platform. Overall, 267 patients aged 65 and over, without severe cognitive impairment (i.e. Mini Mental Status Examination > 20 and CDR<1), no physical disability (i.e. Activities of Daily Living ≥ 5) and no active cancer history (over the past 12 months) were included in 2013. Receiver operating characteristic (ROC) analyses were used to assess the predictive validity of the French version of the MNA-SF for good nutritional status (defined as a full MNA score≥24/30). Analyses were conducted in the overall sample and then in subgroups of frail and pre-frail subjects according to the frailty phenotype. Optimal cut-off points were determined to obtain the best sensitivity/specificity ratio and the highest number of correctly classified subjects. Among 267 patients, mean age=81.5±5.8; women=67.0%; 138 (51.7%) were frail, 98 (36.7%) were pre-frail and 31 (11.6%) were robust. Given their MNA-SF scores, 201 (75.3%) had a good nutritional status, 61 (22.8%) were at risk of malnutrition and 5 (1.9%) were malnourished. In the overall sample, but also in subgroups of pre-frail or frail elders, the areas under ROC curves were 0.954, 0.948 and 0.958 respectively. The 11 points cut-off provided the best correct classification ratio (91.4%); sensitivity=94.0%, specificity=83.3%. The MNA-SF appeared to be a validated and effective tool for malnutrition screening in frail elders. Implementing this tool in clinical routine should contribute to improving the screening of malnourished frail individuals.

Background Increasing evidence supports the use of plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation for diagnosis of dementia. However, their performance for positive and differential diagnosis of dementia with Lewy bodies (DLB) in clinical settings is still uncertain. Methods We conducted a retrospective biomarker study in two tertiary memory centers, Paris Lariboisière and CM2RR Strasbourg, France, enrolling patients with DLB ( n  = 104), Alzheimer’s disease (AD, n  = 76), and neurological controls (NC, n  = 27). Measured biomarkers included plasma Aβ40/Aβ42 ratio, p-tau181, NfL, and GFAP using SIMOA and plasma YKL-40 and sTREM2 using ELISA. DLB patients with available CSF analysis ( n  = 90) were stratified according to their CSF Aβ profile. Results DLB patients displayed modified plasma Aβ ratio, p-tau181, and GFAP levels compared with NC and modified plasma Aβ ratio, p-tau181, GFAP, NfL, and sTREM2 levels compared with AD patients. Plasma p-tau181 best differentiated DLB from AD patients (ROC analysis, area under the curve [AUC] = 0.80) and NC (AUC = 0.78), and combining biomarkers did not improve diagnosis performance. Plasma p-tau181 was the best standalone biomarker to differentiate amyloid-positive from amyloid-negative DLB cases (AUC = 0.75) and was associated with cognitive status in the DLB group. Combining plasma Aβ ratio, p-tau181 and NfL increased performance to identify amyloid copathology (AUC = 0.79). Principal component analysis identified different segregation patterns of biomarkers in the DLB and AD groups. Conclusions Amyloid, tau, neurodegeneration and neuroinflammation plasma biomarkers are modified in DLB, albeit with moderate diagnosis performance. Plasma p-tau181 can contribute to identify Aβ copathology in DLB.

Background Parkinson’s disease (PD) is associated with a 3-fold mortality risk, which is closely related to advancing age. Evidence is lacking regarding the factors associated with the risks of mortality or nursing-home (NH) admission, in elderly patients with PD. We aimed at identifying the clinical characteristics associated with these outcomes, in older community-dwelling patients with late-onset PD. Methods Retrospective, observational analysis of data from geriatric day hospital patients. Motor assessment included Unified Parkinson Disease Rating Scale (UPDRS) part III score, Tinetti Performance Oriented Mobility Assessment (POMA) balance and gait tests, and gait speed. Levodopa equivalent dose, comorbidity, cognitive performance, Activities of Daily Living performance were examined. Cox proportional hazards models were performed to identify the factors associated with mortality and NH admission rate (maximum follow-up time = 5 years). Results We included 98 patients, mean age 79.4 (SD = 5.3) of whom 18 (18.3%) died and 19 (19.4%) were admitted into NH, over a median follow-up of 4 years. In multivariate Cox models, poor balance on the Tinetti POMA scale (HR = 0.82 95%CI (0.66–0.96), p  = .023) and older age (HR = 1.12 95%CI (1.01–1.25), p  = .044) were the only variables significantly associated with increased mortality risk. A Tinetti balance score below 11/16 was associated with a 6.7 hazard for mortality ( p  = .006). No specific factor was associated with NH admissions. Conclusions Age and the Tinetti POMA score were the only factors independently associated with mortality. The Tinetti POMA scale should be considered for balance assessment and as a screening tool for the most at-risk individuals, in this population.

To examine whether the Mini Nutritional Assessment-Short Form (MNA-SF) score and its individual items are predictors of mortality in a nursing home population. Prospective, secondary analysis from the Incidence of pNeumonia and related ConseqUences in nursing home Residents (INCUR) study with 1-year follow-up. A total of 773 older persons (women 74.4%) living in 13 French nursing homes. At baseline, nutritional status was assessed with the MNA-SF. Overall mortality rate was measured over a 12-month follow-up period after the baseline assessment visit. Cox proportional hazard models were performed to test the predictive capacity of the MNA-SF score and its single components for mortality. Mean age of participants was 86.2 (standard deviation, SD 7.5) years. Mean MNA-SF score was 9.8 (SD 2.4). Among participants, 198 (25.6%) presented a normal nutritional status (12–14 points), 454 (58.7%) were at risk of malnutrition (8–11 points), and 121 (15.7%) were malnourished. After one year of follow-up, 135 (17.5%) participants had died. Age, female gender, baseline weight, BMI and MNA-SF were significant predictors of mortality whereas no specific chronic disease was. The total MNA-SF score was a significant predictor of mortality (Hazard Ratio=0.83; 95% CI 0.75–0.91; p<0.001), even after adjustment for potential confounders. Four individual items: weight loss, decrease in food intake, recent stress and BMI were independent predictors of mortality. The MNA-SF appears to be an accurate predictor of one-year mortality in nursing home residents. Thus, this tool may be regarded not only as a nutritional screening tool, but also as an instrument for identifying the most-at-risk individuals in this population.

To investigate the relationship between cerebrospinal fluid (CSF) β-amyloid peptide (Aβ42) and CSF Tau in a large population of patients referred to memory clinics for investigation of cognitive dysfunction. We analyzed Alzheimer's disease (AD) biomarkers in CSF taken from 3565 patients referred to 18 French memory clinics. Patients were classified into four profiles according to levels of CSF biomarkers (A: amyloidosis, N: neurodegeneration). The association between CSF Tau and CSF Aβ42 were analyzed using general linear regression models, in the overall population and stratified by biomarkers profiles. We compared linear and quadratic models using Akaike information criterion. We also assessed change in biomarker profiles in a subset of patients who had 2 assessments of biomarkers. CSF Tau was negatively associated with CSF Aβ42 in the overall population, following a non-linear quadratic model. However, the nature of this association was different in the 4 profiles: positive association in A-N- profile, negative association in A-N+ and A+N+ profiles, lack of association in A+N- patients. When considering patients with longitudinal data on profiles, 36% of those initially classified as A-N+ evolved to an A+N+ profile. The nature of the association between CSF Aβ42 and CFS Tau depends on the A/N profiles of patients. These results suggest an increase in CSF Aβ42 early in the disease before its decline while tau pathology progresses, this pattern is particularly observed in non-APOE4 subjects. This phenomenon may explain why some patients with neurodegeneration only markers convert to an AD profile (A+N+) over time.

Background Anticholinergic medications are widely prescribed to older adults and are linked to increased mortality and cognitive decline. Cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD)—amyloid and tau—are strong prognostic indicators in neurocognitive disorders (NCD). However, it remains unclear whether anticholinergic burden amplifies mortality risk depending on CSF biomarker profiles in cognitively impaired individuals. Methods We conducted a retrospective monocentric study of 927 patients aged ≥ 65 years with mild or major NCD from a tertiary memory clinic in Paris, France. Participants underwent CSF biomarker assessment for amyloid (A), phosphorylated tau (T), and total tau (N), and were classified into ATN profiles. Anticholinergic burden was evaluated at baseline using the Anticholinergic Cognitive Burden (ACB) scale: none (ACB = 0), low–moderate (ACB = 1–2), or high (ACB ≥ 3). The primary outcome was all-cause mortality. Proportional hazards regression assessed associations between ACB, ATN profiles, and mortality, adjusting for demographic, clinical, and genetic covariates. Results High ACB was associated with increased mortality in model 1 (HR = 1.30, 95% CI: 1.03–1.64, p  = 0.02), but not after full adjustment (HR = 1.26, 95% CI: 0.96–1.66, p  = 0.09). ATN profiles remained strong independent predictors of mortality, with highest risks for A–T–N + and A + T + Nx profiles. Combined high ACB and abnormal biomarkers conferred greater risk than either alone (e.g., HR = 2.24 for A + T + Nx and high ACB). Conclusion Anticholinergic burden may increase vulnerability to mortality in older adults with an AD biomarker profile. These results support integrating pharmacological and biological risk factors into personalized dementia care.

Background Core cerebrospinal fluid (CSF) amyloid and tau biomarker assessment has been recommended to refine the diagnostic accuracy of Alzheimer’s disease. Lumbar punctures (LP) are invasive procedures that might induce anxiety and pain. The use of non-pharmacological techniques must be considered to reduce the patient’s discomfort, in this setting. The objective of this study was to examine the efficacy of hypnosis on anxiety and pain associated with LP. Methods A monocentric interventional randomized-controlled pilot study is conducted in a university geriatric day hospital. Cognitively impaired patients aged over 70 were referred for scheduled LP for the diagnostic purpose (CSF biomarkers). The participants were randomly assigned either to a hypnosis intervention group or usual care. Pain and anxiety were both self-assessed by the patient and hetero-evaluated by the operator. Results We included 50 cognitively impaired elderly outpatients (women 54%, mean age 77.2 ± 5.0, mean Mini-Mental State Examination score 23.2 ± 3.5). Hypnosis was significantly associated with reduced self-assessed ( p < 0.05) and hetero-assessed anxiety ( p < 0.01). Hetero-evaluated pain was significantly lower in the hypnosis group ( p < 0.05). The overall perception of hypnosis was safe, well-accepted, and feasible in all the participants of the intervention group with 68% perceiving the procedure as better or much better than expected. Conclusions This pilot study suggested that hypnosis was feasible and may be used to reduce the symptoms of discomfort due to invasive procedures in older cognitively impaired patients. Our results also confirmed the overall good acceptance of LP in this population, despite the usual negative perception. Trial registration ClinicalTrials.gov NCT04368572. Registered on April 30, 2020.