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SummaryTreatment of older adults with hip fracture is a healthcare challenge. Orthogeriatric comanagement that is an integrated model of care with shared responsibility improves time to surgery and reduces the length of hospital stay and mortality compared with orthopedic care with geriatric consultation service and usual orthopedic care, respectively.IntroductionTreatment of fractures in older adults is a clinical challenge due partly to the presence of comorbidity and polypharmacy. The goal of orthogeriatric models of care is to improve clinical outcomes among older people with hip fractures. We compare clinical outcomes of persons with hip fracture cared according to orthogeriatric comanagement (OGC), orthopedic team with the support of a geriatric consultant service (GCS), and usual orthopedic care (UOC).MethodsThis is a single-center, pre-post intervention observational study with two parallel arms, OGC and GCS, and a retrospective control arm. Hip fracture patients admitted to the trauma ward were assigned by the orthopedic surgeon to the OGC (n = 112) or GCS (n = 108) group. The intervention groups were compared each with others and both with the retrospective control group (n = 210) of older adults with hip fracture. Several clinical indicators are considered, including time to surgery, length of stay, in-hospital, and 1-year mortality.ResultsPatients in the OGC (OR 2.62; CI 95% 1.40–4.91) but not those in the GCS (OR 0.74; CI 95% 0.38–1.47) showed a higher probability of undergoing surgery within 48 h compared with those in the UOC. Moreover, the OGC (β, − 1.08; SE, 0.54, p = 0.045) but not the GCS (β, − 0.79; SE, 0.53, p = 0.148) was inversely associated with LOS. Ultimately, patients in the OGC (OR 0.31; CI 95 % 0.10–0.96) but not those in the GCS (OR 0.37; CI 95% 0.10–1.38) experienced a significantly lower 1-year mortality rate compared with those in the UOC. All analyses were independent of several confounders.ConclusionsOlder adults with hip fracture taken in care by the OGC showed better clinical indicators, including time to surgery, length of stay and mortality, than those managed by geriatric consultant service or usual orthopedic care.

SummaryThis study investigates the relationship between cognitive dysfunction or delirium detected in the early post-surgical phase and the 1-year mortality among 514 hip fracture hospitalized older persons. Patients with early cognitive dysfunction or delirium experienced a 2-fold increased mortality risk. Early post-operative cognitive dysfunction and delirium are negative prognostic factors for mortality.Background and purposePremorbid cognitive impairment and dementia in older individuals negatively affect functional recovery after hip fracture. Additionally, post-operative delirium is an established risk factor for negative outcomes among hip fracture patients. While the majority of hip fracture patients experience minor post-surgical cognitive dysfunction, the prognostic value of this phenomenon is unknown. Therefore, we investigated the relationship between minor cognitive dysfunction or delirium detected in the early post-surgical phase and the 1-year mortality after index hip fracture.Subjects and methodsWe enrolled 514 patients with hip fracture (77.4 % women), aged 65 years or older (mean age 83.1 ± 7.3 years), who underwent surgical hip fracture repair. Patients were assessed daily from the second to the fourth post-operative day and at 3, 6, and 12 months thereafter. All participants underwent comprehensive assessment, including detection of delirium by using the confusion assessment method and evaluation of cognitive function by using mini-mental state examination (MMSE; score range 0 to 30, with lower scores indicating poorer performance). In the absence of delirium, post-surgical cognitive dysfunction was defined as having low performance on MMSE. Vital status of 1 year after the index fracture and date of death were gathered from local registries.ResultsThe observed 1-year mortality rate was 14.8 %. Men were more likely to die than women within 1 year of the index fracture (p < 0.01). Compared to participants with better cognitive performance, those with MMSE < 24, as well as those with delirium in the post-operative phase, showed a significantly higher 1-year mortality rate (23.3 versus 17.9 and 8.1 %, respectively). Independent of age and sex, post-operative cognitive dysfunction as well as delirium was both associated with a 2-fold increased mortality risk.ConclusionsThe presence of minor cognitive dysfunction in the early post-surgical phase is a negative prognostic factor for mortality among elderly hip fracture patients. The burden of minor cognitive dysfunction is likely superimposed on that of delirium in subgroups of frail patients.

Graph analysis has become a popular approach to study structural brain networks in neurodegenerative disorders such as Alzheimer’s disease (AD). However, reported results across similar studies are often not consistent. In this paper we investigated the stability of the graph analysis measures clustering, path length, global efficiency and transitivity in a cohort of AD ( N  = 293) and control subjects ( N  = 293). More specifically, we studied the effect that group size and composition, choice of neuroanatomical atlas, and choice of cortical measure (thickness or volume) have on binary and weighted network properties and relate them to the magnitude of the differences between groups of AD and control subjects. Our results showed that specific group composition heavily influenced the network properties, particularly for groups with less than 150 subjects. Weighted measures generally required fewer subjects to stabilize and all assessed measures showed robust significant differences, consistent across atlases and cortical measures. However, all these measures were driven by the average correlation strength, which implies a limitation of capturing more complex features in weighted networks. In binary graphs, significant differences were only found in the global efficiency and transitivity measures when using cortical thickness measures to define edges. The findings were consistent across the two atlases, but no differences were found when using cortical volumes. Our findings merits future investigations of weighted brain networks and suggest that cortical thickness measures should be preferred in future AD studies if using binary networks. Further, studying cortical networks in small cohorts should be complemented by analyzing smaller, subsampled groups to reduce the risk that findings are spurious.

Several chemical substances belonging to classes of natural dietary origin display protective properties against some age-related diseases including neurodegenerative ones, particularly Alzheimer's disease (AD). These compounds, known as nutraceuticals, differ structurally, act therefore at different biochemical and metabolic levels and have shown different types of neuroprotective properties. The aim of this review is to summarize data from observational studies, clinical trials, and randomized clinical trials (RCTs) in humans on the effects of selected nutraceuticals against age-related cognitive impairment and dementia. We report results from studies on flavonoids, some vitamins and other natural substances that have been studied in AD and that might be beneficial for the maintenance of a good cognitive performance. Due to the substantial lack of high-level evidence studies there is no possibility for recommendation of nutraceuticals in dementia-related therapeutic guidelines. Nevertheless, the strong potential for their neuroprotective action warrants further studies in the field.

Background Skeletal muscle is the main source of circulating irisin, both at rest and during physical activity. Previous studies have suggested that irisin can improve cognitive abilities. Aims We explored whether six months of Tai Chi (TC) practice can modulate such a relationship in healthy older persons. Methods This is a prospective clinical study to evaluate the effects of TC practice as compared with low intensity exercise (LI) and no exercise (NE) control groups on plasmatic irisin levels and cognitive performance. Forty-two healthy older persons were stratified into three groups according to physical activities. Biochemical assay and cognitive functions were assessed at the baseline and after six months. Results A significant change was found in circulating irisin levels in TC as compared with NE group ( p  = 0.050) across time. At six months in TC group irisin levels significantly correlated with a verbal memory test ( p  = 0.013) controlled by age and education. Conclusion Our results suggest the potential benefits for cognitive health of TC practice by irisin levels modulation.

Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E ( APOE) ɛ4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ɛ3 homozygous male Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as ‘probably damaging’ missense variants were rs9610775 ( CARD10 ) and rs1136410 ( PARP1 ). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ɛ3/ɛ3 group ( N =315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ɛ3/ɛ3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ɛ3/ɛ3 individuals ( N =923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

There is an urgent need for the identification of Alzheimer’s disease (AD) biomarkers. Studies have now suggested the promising use of associations with blood metabolites as functional intermediate phenotypes in biomedical and pharmaceutical research. The aim of this study was to use lipidomics to identify a battery of plasma metabolite molecules that could predict AD patients from controls. We performed a comprehensive untargeted lipidomic analysis, using ultra-performance liquid chromatography/mass spectrometry on plasma samples from 35 AD patients, 40 elderly controls and 48 individuals with mild cognitive impairment (MCI) and used multivariate analysis methods to identify metabolites associated with AD status. A combination of 10 metabolites could discriminate AD patients from controls with 79.2% accuracy (81.8% sensitivity, 76.9% specificity and an area under curve of 0.792) in a novel test set. Six of the metabolites were identified as long chain cholesteryl esters (ChEs) and were reduced in AD (ChE 32:0, odds ratio (OR)=0.237, 95% confidence interval (CI)=0.10–0.48, P =4.19E−04; ChE 34:0, OR=0.152, 95% CI=0.05–0.37, P =2.90E−04; ChE 34:6, OR=0.126, 95% CI=0.03–0.35, P =5.40E−04; ChE 32:4, OR=0.056, 95% CI=0.01–0.24, P =6.56E−04 and ChE 33:6, OR=0.205, 95% CI=0.06–0.50, P =2.21E−03, per (log2) metabolite unit). The levels of these metabolites followed the trend control>MCI>AD. We, additionally, found no association between cholesterol, the precursor of ChE and AD. This study identified new ChE molecules, involved in cholesterol metabolism, implicated in AD, which may help identify new therapeutic targets; although, these findings need to be replicated in larger well-phenotyped cohorts.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with considerable evidence suggesting an initiation of disease in the entorhinal cortex and hippocampus and spreading thereafter to the rest of the brain. In this study, we combine genetics and imaging data obtained from the Alzheimer's Disease Neuroimaging Initiative and the AddNeuroMed study. To identify genetic susceptibility loci for AD, we conducted a genome-wide study of atrophy in regions associated with neurodegeneration in this condition. We identified one single-nucleotide polymorphism (SNP) with a disease-specific effect associated with entorhinal cortical volume in an intron of the ZNF292 gene (rs1925690; P -value=2.6 × 10 −8 ; corrected P -value for equivalent number of independent quantitative traits=7.7 × 10 −8 ) and an intergenic SNP, flanking the ARPP-21 gene, with an overall effect on entorhinal cortical thickness (rs11129640; P -value=5.6 × 10 −8 ; corrected P -value=1.7 × 10 −7 ). Gene-wide scoring also highlighted PICALM as the most significant gene associated with entorhinal cortical thickness ( P -value=6.7 × 10 −6 ).

The use of drugs with intrinsic anticholinergic properties is widespread among old age persons. A growing body of evidences suggest that a high anticholinergic burden is associated with physical and cognitive impairment. However, the association between anticholinergic drug use and functional status is still poorly investigated, particularly among subjects with initial cognitive impairment. Cross-sectional study examining the association between drug-related anticholinergic burden and functional status in cognitively healthy (CH) (n=691), mild cognitive impairment (MCI) (n=541) or mild Alzheimer's diseases (AD) (n=1127) subjects. Data were gathered from the ReGAl project (Rete Geriatrica Alzheimer-Geriatric Network on Alzheimer's disease), a large longitudinal Italian multicentric clinical-based study, promoted by the Italian Society of Gerontology and Geriatrics (SIGG). 2359 outpatients, older than 65 years, admitted to memory clinics. The total sample size, estimated according to a global effect size of 25% with type I error of 0.05 and a power of 95% is 2010 subjects. Functional status was evaluated by the Katz Index of Independence in Activities of Daily Living (ADL) and the Lawton-Brody Instrumental Activities of Daily Living (IADL) scales. The drug-related anticholinergic burden was estimated by the Anticholinergic Risk Scale (ARS). The 15.9 % (n=375) of total population used at least one drug with anticholinergic properties. Such a drug use was associated with partially dependence in ADL (OR:1.42, CI95%: 1.10-1.83; p=0.006), independently of gender, number of drugs, comorbidity index, presence of clinically relevant neuropsychiatric symptoms and adjusted MMSE. Anticholinergic drug use was associated with un-ability at each IADL task only in male MCI subjects, with significant impairment in shopping (p=0.011), and drug management (p=0.05). The use of medications with anticholinergic properties is common among older persons cognitively health as well as with cognitive impairment. Our results suggest that the use of anticholinergic drugs is associated with functional impairment, especially in old age subjects with initial cognitive impairment. Minimizing anticholinergic burden should result in maintaining daily functioning, especially in a vulnerable population, such as MCI and mild AD.

Memory impairment is the cardinal early feature of Alzheimer’s disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an integrative genomics approach to perform the largest study to date of human memory ( n =14 781). Using a genome-wide screen, we discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2; rs7594645-G) with better memory performance and replicated this finding in independent samples. Consistent with a neuroprotective effect, rs7594645-G carriers exhibited increased hippocampal volume and gray matter density and decreased cerebrospinal fluid levels of apoptotic mediators. The MTOR (mechanistic target of rapamycin) gene and pathways related to endocytosis, cholinergic neurotransmission, epidermal growth factor receptor signaling and immune regulation, among others, also displayed association with memory. These findings nominate FASTKD2 as a target for modulating neurodegeneration and suggest potential mechanisms for therapies to combat memory loss in normal cognitive aging and dementia.