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The precise diagnostics of complex diseases require to integrate a large amount of information from heterogeneous clinical and biomedical data, whose direct and indirect interdependences are notoriously difficult to assess. To this end, we propose an efficient computational approach to simultaneously compute and assess the significance of multivariate information between any combination of mixed-type (continuous/categorical) variables. The method is then used to uncover direct, indirect and possibly causal relationships between mixed-type data from medical records, by extending a recent machine learning method to reconstruct graphical models beyond simple categorical datasets. The method is shown to outperform existing tools on benchmark mixed-type datasets, before being applied to analyze the medical records of eldery patients with cognitive disorders from La Pitié-Salpêtrière Hospital, Paris. The resulting clinical network visually captures the global interdependences in these medical records and some facets of clinical diagnosis practice, without specific hypothesis nor prior knowledge on any clinically relevant information. In particular, it provides some physiological insights linking the consequence of cerebrovascular accidents to the atrophy of important brain structures associated to cognitive impairment.

Elderly patients with hip fracture have a 5 to 8 fold increased risk of death during the months following surgery. We tested the hypothesis that early geriatric management of these patients focused on co-morbidities and rehabilitation improved long term mortality. In a cohort study over a 6 year period, we compared patients aged >70 years with hip fracture admitted to orthopedic versus geriatric departments in a time series analysis corresponding to the creation of a dedicated geriatric unit. Co-morbidities were assessed using the Cumulative Illness Rating Scale (CIRS). Each cohort was compared to matched cohorts extracted from a national registry (n = 51,275) to validate the observed results. Main outcome measure was 6-month mortality. We included 131 patients in the orthopedic cohort and 203 in the geriatric cohort. Co-morbidities were more frequent in the geriatric cohort (median CIRS: 8 vs 5, P<0.001). In the geriatric cohort, the proportion of patients who never walked again decreased (6% versus 22%, P<0.001). At 6 months, re-admission (14% versus 29%, P = 0.007) and mortality (15% versus 24%, P = 0.04) were decreased. When co-morbidities were taken into account, the risk ratio of death at 6 months was reduced (0.43, 95%CI 0.25 to 0.73, P = 0.002). Using matched cohorts, the average treatment effects on the treated associated to early geriatric management indicated a reduction in hospital mortality (-63%; 95% CI: -92% to -6%, P = 0.006). Early admission to a dedicated geriatric unit improved 6-month mortality and morbidity in elderly patients with hip fracture.

Background Recent international guidelines emphasize a multidisciplinary, patient-centered approach to managing atrial fibrillation (AF), particularly regarding antithrombotic (antiplatelet and anticoagulant) management. These guidelines advocate establishing multidisciplinary AF teams, but the clinical benefits of this approach for high-risk, clinically complex subgroups—particularly among very old and frail patients—remain uncertain. Our objective was to evaluate the impact of a hospital multidisciplinary team meeting dedicated to antithrombotics management on a composite measure of all-cause death, major thromboembolic events, or major or clinically relevant bleeding within 6 months in older adults with AF. Methods A prospective multicenter cohort study was conducted in five acute geriatric departments in the Paris area between May 2021 and January 2024. Using a target trial emulation approach (cloning, censoring, weighting strategies), outcomes were analyzed in patients aged ≥ 75 years with AF or atrial flutter, followed in the geriatric departments (via outpatient consultation or hospitalization; > 98% were hospitalized). Participants were followed for 6 months or until death. The primary exposure was a hospital multidisciplinary team meeting within 45 days of inclusion, involving geriatricians, cardiologists, neurovascular specialists, and hemostasis experts. Cumulative incidences were estimated using the reverse Kaplan–Meier method.  Results The study included 818 patients, 138 (16.9%) in the hospital multidisciplinary-team meeting arm (median age 89 (Q1Q3 84–93), 57% female). The 6-month cumulative incidence of the primary composite outcome was 35.3% (95% CI, 29.6 to 41.8) in the multidisciplinary-team meeting arm and 36.2% (95% CI, 32.2 to 40.1) in the control arm (risk difference − 0.9 (95% CI, − 7.5 to 6.0); p  = .79). The 2 arms did not differ in individual events within the composite measure. Conclusions A hospital multidisciplinary team meeting dedicated to antithrombotics management in older adults with AF was not associated with a reduction in all-cause death, major thromboembolic events, or major or clinically relevant bleeding within 6 months. These findings should be interpreted with caution due to the observational design and potential for residual confounding. Trial registration ClinicalTrials.gov registration: NCT04932603. 

Background Isolated subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are the prodromal phases of dementia with Lewy bodies (DLB). MEMENTO is a nationwide study of patients with SCI and MCI with clinic, neuropsychology, biology, and brain imaging data. We aimed to compare SCI and MCI patients with symptoms of prodromal DLB to others in this study at baseline. Methods Participants of the French MEMENTO cohort study were recruited for either SCI or MCI. Among them, 892 were included in the Lewy sub-study, designed to search specifically for symptoms of DLB. Probable prodromal DLB diagnosis (pro-DLB group) was done using a two-criteria cutoff score among the four core clinical features of DLB. This Pro-DLB group was compared to two other groups at baseline: one without any core symptoms (NS group) and the one with one core symptom (1S group). A comprehensive cognitive battery, questionnaires on behavior, neurovegetative and neurosensory symptoms, brain 3D volumetric MRI, CSF, FDG PET, and amyloid PET were done. Results The pro-DLB group comprised 148 patients (16.6%). This group showed more multidomain (59.8%) MCI with slower processing speed and a higher proportion of patients with depression, anxiety, apathy, constipation, rhinorrhea, sicca syndrome, and photophobia, compared to the NS group. The pro-DLB group had isolated lower P-Tau in the CSF (not significant after adjustments for confounders) and on brain MRI widening of sulci including fronto-insular, occipital, and olfactory sulci (FDR corrected), when compared to the NS group. Evolution to dementia was not different between the three groups over a median follow-up of 2.6 years. Conclusions Patients with symptoms of prodromal DLB are cognitively slower, with more behavioral disorders, autonomic symptoms, and photophobia. The occipital, fronto-insular, and olfactory bulb involvement on brain MRI was consistent with symptoms and known neuropathology. The next step will be to study the clinical, biological, and imaging evolution of these patients. Trial registration Clinicaltrials.gov , NCT01926249

Helping neurons to compensate for proteotoxic stress and maintain function over time (neuronal compensation) has therapeutic potential in aging and neurodegenerative disease. The stress response factor FOXO3 is neuroprotective in models of Huntington’s disease (HD), Parkinson’s disease and motor-neuron diseases. Neuroprotective compounds acting in a FOXO-dependent manner could thus constitute bona fide drugs for promoting neuronal compensation. However, whether FOXO-dependent neuroprotection is a common feature of several compound families remains unknown. Using drug screening in C. elegans nematodes with neuronal expression of human exon-1 huntingtin (128Q), we found that 3ß-Methoxy-Pregnenolone (MAP4343), 17ß-oestradiol (17ßE2) and 12 flavonoids including isoquercitrin promote neuronal function in 128Q nematodes. MAP4343, 17ßE2 and isoquercitrin also promote stress resistance in mutant Htt striatal cells derived from knock-in HD mice. Interestingly, daf-16 /FOXO is required for MAP4343, 17ßE2 and isoquercitrin to sustain neuronal function in 128Q nematodes. This similarly applies to the GSK3 inhibitor lithium chloride (LiCl) and, as previously described, to resveratrol and the AMPK activator metformin. Daf-16/FOXO and the targets engaged by these compounds define a sub-network enriched for stress-response and neuronally-active pathways. Collectively, these data highlights the dependence on a daf-16 /FOXO-interaction network as a common feature of several compound families for prolonging neuronal function in HD.

Background Several multicenter randomized controlled trials comparing laparoscopy and conventional open surgery for colon cancer have demonstrated that laparoscopic approach achieved the same oncological results while improving significantly early postoperative outcomes. These trials included few elderly patients, with a median age not exceeding 71 years. However, colon cancer is a disease of the elderly. More than 65% of patients operated on for colon cancer belong to this age group, and this proportion may become more pronounced in the coming years. In current practice, laparoscopy is underused in this population. Methods The CELL (Colectomy for cancer in the Elderly by Laparoscopy or Laparotomy) trial is a multicenter, open-label randomized, 2-arm phase III superiority trial. Patients aged 75 years or older with uncomplicated colonic adenocarcinoma or endoscopically unresectable colonic polyp will be randomized to either colectomy by laparoscopy or laparotomy. The primary endpoint of the study is overall postoperative morbidity, defined as any complication classification occurring up to 30 days after surgery. The secondary endpoints are: 30-day and 90-day postoperative mortality, 30-day readmission rate, quality of surgical resection, health-related quality of life and evolution of geriatric assessment. A 35 to 20% overall postoperative morbidity rate reduction is expected for patients operated on by laparoscopy compared with those who underwent surgery by laparotomy. With a two-sided α risk of 5% and a power of 80% (β = 0.20), 276 patients will be required in total. Discussion To date, no dedicated randomized controlled trial has been conducted to evaluate morbidity after colon cancer surgery by laparoscopy or laparotomy in the elderly and the benefits of laparoscopy is still debated in this context. Thus, a prospective multicenter randomized trial evaluating postoperative outcomes specifically in elderly patients operated on for colon cancer by laparoscopy or laparotomy with curative intent is warranted. If significant, such a study might change the current surgical practices and allow a significant improvement in the surgical management of this population, which will be the vast majority of patients treated for colon cancer in the coming years. Trial registration ClinicalTrials.gov NCT03033719 (January 27, 2017).

The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α ≥ 0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80-0.93), and moderate (Intra-class coefficient = 0.54-0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho ≥ 0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar. The NNIPPS-PPS has suitable validity, is reliable and sensitive, and therefore is appropriate for use in clinical studies with PSP or MSA. ClinicalTrials.gov NCT00211224.

During visual fixation, the eyes are never completely still, but produce small involuntary movements, called “fixational eye movements,” including microsaccades, drift, and tremor. In certain neurological disorders, attempted fixation results in abnormal fixational eye movements with distinctive characteristics. Thus, determining how normal fixation differs from pathological fixation has the potential to aid early and differential noninvasive diagnosis of neurological disease as well as the quantification of its progression and response to treatment. Here, we recorded the eye movements produced by patients with Alzheimer’s disease, patients with mild cognitive impairment, and healthy age-matched individuals during attempted fixation. We found that microsaccade magnitudes, velocities, durations, and intersaccadic intervals were comparable in the three subject groups, but microsaccade direction differed in patients versus healthy subjects. Our results indicate that microsaccades are more prevalently oblique in patients with Alzheimer’s disease or mild cognitive impairment than in healthy subjects. These findings extended to those microsaccades paired in square-wave jerks, supporting the hypothesis that microsaccades and square-wave jerks form a continuum, both in healthy subjects and in neurological patients.

Background Several studies have suggested that vascular dysfunction plays an important role in Alzheimer’s disease. Aims We hypothesized that significant differences might be observed in the levels of blood endothelial biomarkers across elderly population of subjects with dementia. Methods We analyzed, in a prospective monocentric study, three different endothelial biomarkers, endothelial microparticles (EMPs), endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) in 132 older patients who underwent a full evaluation of a memory complaint. Results There was no difference in specific EMP, EPC or CEC levels between demented or non-demented patients, nor considering cognitive decline. Discussion Blood endothelial biomarkers may be too sensitive and it is likely that the multimorbidity observed in our patients may lead to opposite and confounding effects on endothelial biomarkers levels. Conclusion Unlike younger AD patients, our results suggest that endothelial biomarkers are not valuable for the diagnosis of dementia in elderly patients.

Background One of the crucial challenges for the future of therapeutic approaches to Alzheimer’s disease (AD) is to target the main pathological processes responsible for disability and dependency. However, a progressive cognitive impairment occurring after the age of 70, the main population affected by dementia, is often related to mixed lesions of neurodegenerative and vascular origins. Whereas young patients are mostly affected by pure lesions, ageing favours the occurrence of co-lesions of AD, cerebrovascular disease (CVD) and Lewy body dementia (LBD). Most of clinical studies report on functional and clinical disabilities in patients with presumed pure pathologies. But, the weight of co-morbid processes involved in the transition from an independent functional status to disability in the elderly with co-lesions still remains to be elucidated. Neuropathological examination often performed at late stages cannot answer this question at mild or moderate stages of cognitive disorders. Brain MRI, Single Photon Emission Computed Tomography (SPECT) with DaTscan®, amyloid Positron Emission Tomography (PET) and CerebroSpinal Fluid (CSF) AD biomarkers routinely help in performing the diagnosis of underlying lesions. The combination of these measures seems to be of incremental value for the diagnosis of mixed profiles of AD, CVD and LBD. The aim is to determine the clinical, neuropsychological, neuroradiological and biological features the most predictive of cognitive, behavioral and functional impairment at 2 years in patients with co-existing lesions. Methods A multicentre and prospective cohort study with clinical, neuro-imaging and biological markers assessment will recruit 214 patients over 70 years old with a cognitive disorder of AD, cerebrovascular and Lewy body type or with coexisting lesions of two or three of these pathologies and fulfilling the diagnostic criteria for dementia at a mild to moderate stage. Patients will be followed every 6 months (clinical, neuropsychological and imaging examination and collection of cognitive, behavioural and functional impairment) for 24 months. Discussion This study aims at identifying the best combination of markers (clinical, neuropsychological, MRI, SPECT-DaTscan®, PET and CSF) to predict disability progression in elderly patients presenting coexisting patterns. Trial registration NCT02052947 .