Validation, Deployment, and Real-World Implementation of a Modular Toolbox for Alzheimer's Disease Detection and Dementia Risk Reduction: The AD-RIDDLE Project.

The Real-World Implementation, Deployment, and Validation of Early Detection Tools and Lifestyle Enhancement (AD-RIDDLE) project, recently launched with the support of the EU Innovative Health Initiative (IHI) public-private partnership and UK Research and Innovation (UKRI), aims to develop, test, and deploy a modular toolbox platform that can reduce existing barriers to the timely detection, and therapeutic approaches in Alzheimer's disease (AD), thus accelerating AD innovation. By focusing on health system and health worker practices, AD-RIDDLE seeks to improve and smooth AD management at and between each key step of the clinical pathway and across the disease continuum, from at-risk asymptomatic stages to early symptomatic ones. This includes innovation and improvement in AD awareness, risk reduction and prevention, detection, diagnosis, and intervention. The 24 partners in the AD-RIDDLE interdisciplinary consortium will develop and test the AD-RIDDLE toolbox platform and its components individually and in combination in six European countries. Expected results from this cross-sectoral research collaboration include tools for earlier detection and accurate diagnosis; validated, novel digital cognitive and blood-based biomarkers; and improved access to individualized preventative interventions (including multimodal interventions and symptomatic/disease-modifying therapies) across diverse populations, within the framework of precision medicine. Overall, AD-RIDDLE toolbox platform will advance management of AD, improving outcomes for patients and their families, and reducing costs.

Dementia, osteoporosis and fragility fractures: Intricate epidemiological relationships, plausible biological connections, and twisted clinical practices.

Dementia, osteoporosis, and fragility fractures are chronic diseases, often co-existing in older adults. These conditions pose severe morbidity, long-term disability, and mortality, with relevant socioeconomic implications. While in the research arena, the discussion remains on whether dementia is the cause or the consequence of fragility fractures, healthcare professionals need a better understanding of the interplay between such conditions from epidemiological and physiological standpoints. With this review, we summarized the available literature surrounding the relationship between cognitive impairment, dementia, and both low bone mineral density (BMD) and fragility fractures. Given the strength of the bi-directional associations and their impact on the quality of life, we shed light on the biological connections between brain and bone systems, presenting the main mediators, including gut microbioma, and pathological pathways leading to the dysregulation of bone and brain metabolism. Ultimately, we synthesized the evidence about the impact of available pharmacological treatments for the prevention of fragility fractures on cognitive functions and individuals' outcomes when dementia coexists. Vice versa, the effects of symptomatic treatments for dementia on the risk of falls and fragility fractures are explored. Combining evidence alongside clinical practice, we discuss challenges and opportunities related to the management of older adults affected by cognitive impairment or dementia and at high risk for fragility fracture prevention, which leads to not only an improvement in patient health-related outcomes and survival but also a reduction in healthcare cost and socio-economic burden.

Semi-quantification and grading of amyloid PET: A project of the European Alzheimer's Disease Consortium (EADC).

BACKGROUND: amyloid-PET reading has been classically implemented as a binary assessment, although the clinical experience has shown that the number of borderline cases is non negligible not only in epidemiological studies of asymptomatic subjects but also in naturalistic groups of symptomatic patients attending memory clinics. In this work we develop a model to compare and integrate visual reading with two independent semi-quantification methods in order to obtain a tracer-independent multi-parametric evaluation. METHODS: We retrospectively enrolled three cohorts of cognitively impaired patients submitted to 18F-florbetaben (53 subjects), 18F-flutemetamol (62 subjects), 18F-florbetapir (60 subjects) PET/CT respectively, in 6 European centres belonging to the EADC. The 175 scans were visually classified as positive/negative following approved criteria and further classified with a 5-step grading as negative, mild negative, borderline, mild positive, positive by 5 independent readers, blind to clinical data. Scan quality was also visually assessed and recorded. Semi-quantification was based on two quantifiers: the standardized uptake value (SUVr) and the ELBA method. We used a sigmoid model to relate the grading with the quantifiers. We measured the readers accord and inconsistencies in the visual assessment as well as the relationship between discrepancies on the grading and semi-quantifications. CONCLUSION: It is possible to construct a map between different tracers and different quantification methods without resorting to ad-hoc acquired cases. We used a 5-level visual scale which, together with a mathematical model, delivered cut-offs and transition regions on tracers that are (largely) independent from the population. All fluorinated tracers appeared to have the same contrast and discrimination ability with respect to the negative-to-positive grading. We validated the integration of both visual reading and different quantifiers in a more robust framework thus bridging the gap between a binary and a user-independent continuous scale.

The orthogeriatric comanagement improves clinical outcomes of hip fracture in older adults.

Treatment 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. INTRODUCTION: Treatment 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). METHODS: This 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. RESULTS: Patients 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 (ß, - 1.08; SE, 0.54, p = 0.045) but not the GCS (ß, - 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. CONCLUSIONS: Older 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.

Anticholinergic Burden and Functional Status in Older People with Cognitive Impairment: Results from the Regal Project.

OBJECTIVE: 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. DESIGN: 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. SETTING: 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). PARTICIPANTS: 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. MEASUREMENT: 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). RESULTS: 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). CONCLUSIONS: 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.

Early post-surgical cognitive dysfunction is a risk factor for mortality among hip fracture hospitalized older persons.

This 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 PURPOSE: Premorbid 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 METHODS: We 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. RESULTS: The 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. CONCLUSIONS: The 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.

Plasma protein biomarkers of Alzheimer's disease endophenotypes in asymptomatic older twins: early cognitive decline and regional brain volumes.

There is great interest in blood-based markers of Alzheimer's disease (AD), especially in its pre-symptomatic stages. Therefore, we aimed to identify plasma proteins whose levels associate with potential markers of pre-symptomatic AD. We also aimed to characterise confounding by genetics and the effect of genetics on blood proteins in general. Panel-based proteomics was performed using SOMAscan on plasma samples from TwinsUK subjects who are asymptomatic for AD, measuring the level of 1129 proteins. Protein levels were compared with 10-year change in CANTAB-paired associates learning (PAL; n = 195), and regional brain volumes (n = 34). Replication of proteins associated with regional brain volumes was performed in 254 individuals from the AddNeuroMed cohort. Across all the proteins measured, genetic factors were found to explain ~26% of the variability in blood protein levels on average. The plasma level of the mitogen-activated protein kinase (MAPK) MAPKAPK5 protein was found to positively associate with the 10-year change in CANTAB-PAL in both the individual and twin difference context. The plasma level of protein MAP2K4 was found to suggestively associate negatively (Q < 0.1) with the volume of the left entorhinal cortex. Future studies will be needed to assess the specificity of MAPKAPK5 and MAP2K4 to eventual conversion to AD.

Practical cut-offs for visual rating scales of medial temporal, frontal and posterior atrophy in Alzheimer's disease and mild cognitive impairment.

BACKGROUND: Atrophy in the medial temporal lobe, frontal lobe and posterior cortex can be measured with visual rating scales such as the medial temporal atrophy (MTA), global cortical atrophy - frontal subscale (GCA-F) and posterior atrophy (PA) scales, respectively. However, practical cut-offs are urgently needed, especially now that different presentations of Alzheimer's disease (AD) are included in the revised diagnostic criteria. AIMS: The aim of this study was to generate a list of practical cut-offs for the MTA, GCA-F and PA scales, for both diagnosis of AD and determining prognosis in mild cognitive impairment (MCI), and to evaluate the influence of key demographic and clinical factors on these cut-offs. METHODS: AddNeuroMed and ADNI cohorts were combined giving a total of 1147 participants (322 patients with AD, 480 patients with MCI and 345 control subjects). The MTA, GCA-F and PA scales were applied and a broad range of cut-offs was evaluated. RESULTS: The MTA scale showed better diagnostic and predictive performances than the GCA-F and PA scales. Age, apolipoprotein E (ApoE) ε4 status and age at disease onset influenced all three scales. For the age ranges 45-64, 65-74, 75-84 and 85-94 years, the following cut-offs should be used. MTA: ≥1.5, ≥1.5, ≥2 and ≥2.5; GCA-F, ≥1, ≥1, ≥1 and ≥1; and PA, ≥1, ≥1, ≥1 and ≥1, respectively, with an adjustment for early-onset ApoE ε4 noncarrier AD patients (MTA: ≥2, ≥2, ≥3 and ≥3; and GCA-F: ≥1, ≥1, ≥2 and ≥2, respectively). CONCLUSIONS: If successfully validated in clinical settings, the list of practical cut-offs proposed here might be useful in clinical practice. Their use might also (i) promote research on atrophy subtypes, (ii) increase the understanding of different presentations of AD, (iii) improve diagnosis and prognosis and (iv) aid population selection and enrichment for clinical trials.

Plasma lipidomics analysis finds long chain cholesteryl esters to be associated with Alzheimer's disease.

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.

Association of increased carotid intima-media thickness and lower plasma levels of vitamin C and vitamin E in old age subjects: implications for Alzheimer's disease.

In light of the recent advances regarding the role of vascularity in Alzheimer's disease (AD) pathophysiology, the relationship between plasma levels and activities of the major antioxidant molecules and the carotid intima-media thickness (C-IMT) of older persons with no or very mild cognitive impairment was evaluated. The underlying hypothesis is that the IMT may be an indirect index of vascular damage in persons with low levels of plasma antioxidants. Plasma levels of vitamins A, C, E, of uric acid as well as activities of the plasma antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured. Plasma levels of vitamins C and E significantly decreased among participants from the first to the fourth IMT quartile, with a linear slope only for vitamin C. Compared to participants in the lowest vitamin C quartile, the probability to have IMT >1.2 mm significantly decreased among persons from the second to the fourth quartile independent of confounders. In conclusion, only vitamin C plasma levels appear to be selectively associated with the risk of increasing C-IMT. An adequate vitamin C status might be particularly important for protection against AD and other clinical manifestations of vascular and cognitive ageing.

FASTKD2 is associated with memory and hippocampal structure in older adults.

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.

Random Forest ensembles for detection and prediction of Alzheimer's disease with a good between-cohort robustness.

Computer-aided diagnosis of Alzheimer's disease (AD) is a rapidly developing field of neuroimaging with strong potential to be used in practice. In this context, assessment of models' robustness to noise and imaging protocol differences together with post-processing and tuning strategies are key tasks to be addressed in order to move towards successful clinical applications. In this study, we investigated the efficacy of Random Forest classifiers trained using different structural MRI measures, with and without neuroanatomical constraints in the detection and prediction of AD in terms of accuracy and between-cohort robustness. From The ADNI database, 185 AD, and 225 healthy controls (HC) were randomly split into training and testing datasets. 165 subjects with mild cognitive impairment (MCI) were distributed according to the month of conversion to dementia (4-year follow-up). Structural 1.5-T MRI-scans were processed using Freesurfer segmentation and cortical reconstruction. Using the resulting output, AD/HC classifiers were trained. Training included model tuning and performance assessment using out-of-bag estimation. Subsequently the classifiers were validated on the AD/HC test set and for the ability to predict MCI-to-AD conversion. Models' between-cohort robustness was additionally assessed using the AddNeuroMed dataset acquired with harmonized clinical and imaging protocols. In the ADNI set, the best AD/HC sensitivity/specificity (88.6%/92.0% - test set) was achieved by combining cortical thickness and volumetric measures. The Random Forest model resulted in significantly higher accuracy compared to the reference classifier (linear Support Vector Machine). The models trained using parcelled and high-dimensional (HD) input demonstrated equivalent performance, but the former was more effective in terms of computation/memory and time costs. The sensitivity/specificity for detecting MCI-to-AD conversion (but not AD/HC classification performance) was further improved from 79.5%/75%-83.3%/81.3% by a combination of morphometric measurements with ApoE-genotype and demographics (age, sex, education). When applied to the independent AddNeuroMed cohort, the best ADNI models produced equivalent performance without substantial accuracy drop, suggesting good robustness sufficient for future clinical implementation.

Nutraceuticals in cognitive impairment and Alzheimer's disease.

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.

Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014.

The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or 'mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.

Influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut-offs.

BACKGROUND: Visual assessment of medial temporal lobe atrophy (MTA; range 0-4, from no atrophy to increasing atrophy of the choroid fissure, temporal horns and hippocampus) is a sensitive radiological marker of Alzheimer's disease (AD). One of the critical elements for visual MTA assessment is the cut-off score that determines deviation from normality. METHODS: In this study, we assessed the sensitivity and specificity of different MTA cut-off scores to classify control subjects, individuals with mild cognitive impairment (MCI) and AD patients from two large independent cohorts, AddNeuroMed and Alzheimer's Disease Neuroimaging Initiative. Of note, we evaluated the effects of clinical, demographic and genetic variables on the classification performance according to the different cut-offs. RESULTS: A cut-off of ≥1.5 based on the mean MTA scores of both hemispheres showed higher sensitivity in classifying patients with AD (84.5%) and MCI subjects (75.8%) who converted to dementia compared to an age-dependent cut-off. The age-dependent cut-off showed higher specificity or ability to correctly identify control subjects (83.2%) and those with MCI who remained stable (65.5%). Increasing age, early-onset disease and absence of the ApoE ε4 allele had a stronger influence on classifications using the ≥1.5 cut-off. Above 75 years of age, an alternative cut-off of ≥2.0 should be applied to achieve a classification accuracy for both patients with AD and control subjects that is clinically useful. CONCLUSION: Clinical, demographic and genetic variables can influence the classification of MTA cut-off scores, leading to misdiagnosis in some cases. These variables, in addition to the differential sensitivity and specificity of each cut-off, should be carefully considered when performing visual MTA assessment.

Interaction between bone and muscle in older persons with mobility limitations.

Aging is associated with a progressive loss of bone-muscle mass and strength. When the decline in mass and strength reaches critical thresholds associated with adverse health outcomes, they are operationally considered geriatric conditions and named, respectively, osteoporosis and sarcopenia. Osteoporosis and sarcopenia share many of the same risk factors and both directly or indirectly cause higher risk of mobility limitations, falls, fractures and disability in activities of daily living. This is not surprising since bones adapt their morphology and strength to the long-term loads exerted by muscle during anti-gravitational and physical activities. Non-mechanical systemic and local factors also modulate the mechanostat effect of muscle on bone by affecting the bidirectional osteocyte-muscle crosstalk, but the specific pathways that regulate these homeostatic mechanisms are not fully understood. More research is required to reach a consensus on cut points in bone and muscle parameters that identify individuals at high risk for adverse health outcomes, including falls, fractures and disability. A better understanding of the muscle-bone physiological interaction may help to develop preventive strategies that reduce the burden of musculoskeletal diseases, the consequent disability in older persons and to limit the financial burden associated with such conditions. In this review, we summarize age-related bone-muscle changes focusing on the biomechanical and homeostatic mechanisms that explain bone-muscle interaction and we speculate about possible pathological events that occur when these mechanisms become impaired. We also report some recent definitions of osteoporosis and sarcopenia that have emerged in the literature and their implications in clinical practice. Finally, we outline the current evidence for the efficacy of available anti-osteoporotic and proposed antisarcopenic interventions in older persons.

Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment.

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) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 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 ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 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.

Body mass index, lifestyles, physical performance and cognitive decline: the "Treviso Longeva (TRELONG)" study.

OBJECTIVES: The relative contributions of risk factors, as body mass index (BMI), depression, chronic diseases, smoking, and lifestyles (as physical and performance activity, social contacts and reading habit) to cognitive decline in the elderly are unclear. We explored these variables in relation to 7-year cognitive decline in long-lived Italian elderly. DESIGN: Secondary data analysis of a longitudinal study of a representative, age-stratified, population sample. SETTING: The TREVISO LONGEVA (TRELONG) Study, in Treviso, Italy. PARTICIPANTS: 120 men and 189 women, age 77 years and older (mean age 80.2 ± 6.9 years) survivors after seven years of follow up. MEASUREMENTS: Cognitive decline measured as difference between Mini-Mental State Examination (MMSE) score in 2003 and in 2010; Body mass index (BMI), handgrip, Short Physical Performance Battery (SPPB) score, social contacts, reading habit, sight, hearing, schooling, mediterranean diet and multiple clinical and survey data recorded at baseline in 2003. RESULTS: In separate univariate analyses, age, SPPB score < 5, depressive symptoms (GDS) and more comorbidities (CCI) were associated with greater cognitive decline. Otherwise higher BMI, higher handgrip, reading habit, non-deteriorated sight and hearing, and schooling were protective. In a final multivariate model, age and higher BMI were associated with greater cognitive decline while reading habits was protective. SPPB score < 5 tends, though weakly, to be associated with greater cognitive decline. These associations remained with multivariate adjustment for gender, schooling, Charlson co-morbidity index (CCI) and baseline MMSE. CONCLUSION: Age and higher baseline BMI, independent of gender, and other confounding factors, are risk factors for cognitive decline. Reading habit plays a protective role seven years later among northern Italian adults aged 70 years or older. Low physical performance tends, though weakly, to be associated with greater cognitive decline.

Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of α-/γ-tocotrienols and γ-tocopherol.

BACKGROUND: The aim of this study was to evaluate the accuracy of combined structural magnetic resonance imaging (MRI) measures and plasma levels of vitamin E forms, including all eight natural vitamin E congeners (four tocopherols and four tocotrienols) and markers of vitamin E oxidative/nitrosative damage, in differentiating individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects. METHODS: Overall, 81 patients with AD, 86 with MCI and 86 CTL individuals were enrolled from the longitudinal multicentre AddNeuroMed study. MRI and plasma vitamin E data were acquired at baseline. MRI scans were analysed using Freesurfer, an automated segmentation scheme which generates regional volume and cortical thickness measures. Orthogonal partial least squares to latent structures (OPLS), a multivariate data analysis technique, was used to analyse MRI and vitamin E measures in relation to AD and MCI diagnosis. RESULTS: The joint evaluation of MRI and plasma vitamin E measures enhanced the accuracy of differentiating individuals with AD and MCI from CTL subjects: 98.2% (sensitivity 98.8%, specificity 97.7%) for AD versus CTL, and 90.7% (sensitivity 91.8%, specificity 89.5%) for MCI versus CTL. This combination of measures also identified 85% of individuals with MCI who converted to clinical AD at follow-up after 1 year. CONCLUSIONS: Plasma levels of tocopherols and tocotrienols together with automated MRI measures can help to differentiate AD and MCI patients from CTL subjects, and to prospectively predict MCI conversion into AD. Our results suggest the potential role of nutritional biomarkers detected in plasma-tocopherols and tocotrienols-as indirect indicators of AD pathology, and the utility of a multimodality approach.