Frailty in Caregivers and Its Relationship with Psychological Stress and Resilience: A Cross-SectionalStudy Based on the Deficit Accumulation Model.

BACKGROUND: Studies increasingly suggest that chronic exposure to psychological stress can lead to health deterioration and accelerated ageing, thus possibly contributing to the development of frailty. Recent approaches based on the deficit accumulation model measure frailty on a continuous grading through the "Frailty Index" (FI), i.e. a macroscopic indicator of biological senescence and functional status. OBJECTIVES: The study aimed at testing the relationship of FI with caregiving, psychological stress, and psychological resilience. DESIGN: Cross-sectional study, with case-control and correlational analyses. PARTICIPANTS: Caregivers of patients with dementia (n=64), i.e. individuals a priori considered to be exposed to prolonged psychosocial stressors, and matched controls (n=64) were enrolled. MEASUREMENTS: The two groups were compared using a 38-item FI condensing biological, clinical, and functional assessments. Within caregivers, the association of FI with Perceived Stress Scale (PSS) and Brief Resilience Scale (BRS) was tested. RESULTS: Caregivers had higher FI than controls (F=8.308, p=0.005). FI was associated directly with PSS (r=0.660, p<0.001) and inversely with BRS (r=-0.637, p<0.001). Findings remained significant after adjusting for certain confounding variables, after excluding from the FI the conditions directly related to psychological stress, and when the analyses were performed separately among participants older and younger than 65 years. CONCLUSIONS: The results provide insight on the relationship of frailty with caregiving, psychological stress, and resilience, with potential implications for the clinical management of individuals exposed to chronic emotional strain.

Nutritional Interventions for Early Dementia.

Nutrition plays a critical role in the definition of the individual's wellbeing. Nutritional interventions have been repeatedly advocated as of potential interest for preventing or delaying the cognitive decline, also in the context of neurodegenerative conditions. The idea of targeting the initial phases of dementia, when the process is theoretically still amenable of correction, via lifestyle modifications (including healthy diet or supplementation of specific micro-/macro-nutrients) is extremely appealing. In this perspective paper, we describe the most recent evidence on the topic and discuss how the nutritional assessment should be nested within a comprehensive approach to the aging person with initial signs of dementia for promoting his/her optimal management.

Overtreating Alzheimer's Disease.

The management of frailty in older persons is not easy, implying interventions beyond the simple prescription of medications. Biological complexity, multimorbidity, polypharmacy, and social issues often hamper the possibility to directly translate the evidence coming from research into clinical practice. Frailty indeed represents the most relevant cause of the "evidence-based medicine issue" influencing clinical decisions in geriatric care. Today, patients with Alzheimer's disease (AD) are much older and frailer than some decades ago. They also tend to have more drugs prescribed. In parallel, research on AD has evolved over the years, hypothesizing that anticipating the interventions to the earliest stages of the disease may provide beneficial effects (to date, still lacking). In this article, we argue that, by focusing exclusively on "the disease" and pushing to anticipate its detection (sometimes even before the appareance of its clinical manifestations) may overshadow the person's values and priorities. Research should be developed for better integrating the concept of aging and frailty in the design of clinical trials in order to provide results that can be implemented in real life. On the other hand, clinicians should be less prone to the easy (but unsupported by evidence) pharmacological prescription.

Ongoing Research Protocols for the Pharmacological Treatment of Neuropsychiatric Symptoms in Dementia.

The implementation of effective interventions for neuropsychiatric symptoms (NPS) is perceived as one of the most pressing research priorities in the field of dementia and one of the main unmet needs from the perspective of affected individuals and their caregivers and relatives. Nevertheless, to date, only a relatively marginal part of dementia research has focused on NPS. This study aimed to describe and discuss the state of the art concerning the identification and development of new pharmacological treatments for NPS in dementia. A review of 320 ongoing phase 1, 2, 3, and 4 protocols registered in the clinicaltrials.gov database was performed. All the trials enrolling patients with dementia were selected. Only studies adopting clinical measures of NPS frequency and/or severity as primary outcome were retained and analyzed. Overall, only a minority of ongoing phase 1, 2, 3 and 4 protocols on dementia (i.e., 9.0%) is primarily targeting NPS. Most of these studies are adopting a placebo-controlled parallel assignment design, testing oral compounds, and targeting specific NPS (mostly agitation and/or aggression). A total of 3,445 subjects with dementia will tentatively be recruited in these trials. The methodologies adopted in these studies, the characteristics of the tested interventions, the eligibility criteria, and the operational definitions of NPS are presented and discussed. The relevance of NPS is not yet matched by an adequate research effort. The current tendency at privileging disease-modifying approaches and other symptoms of dementia and the methodological complexity of studying NPS are still substantially contributing to the gap between research activities and clinical needs.

Adopting a Diary to Support an Ecological Assessment of Neuropsychiatric Symptoms of Dementia.

Neuropsychiatric symptoms (NPS) are one of the most challenging issues in the management and care of people with dementia. Their accurate assessment is thus crucial for properly approaching subjects with cognitive disorders in the clinical setting. In parallel, the correct evaluation of NPS is also particularly relevant in the research field where they serve as critical indicators for measuring the efficacy of interventions against cognitive disorders. However, the study of NPS is extremely challenging given their extreme inter- and intra-individual variability. Moreover, the available assessment tools are often inadequate to fully capture their complexity and phenotypic expression. Based on these considerations, novel modalities for the assessment and measurement of NPS may be important to identify and develop. In this regard, a promising alternative (or, at least, a complementary aid) to traditional scales and questionnaires might be constituted by diaries. In the present article, we discuss the potential advantages and implications that may result from the adoption of this kind of instruments for the ecological assessment of NPS in subjects with dementia.

Estimating dementia cases amongst migrants living in Europe.

BACKGROUND AND PURPOSE: The phenomenon of dementia amongst migrants and ethnic minorities represents an emerging concern for European healthcare systems, posing additional challenges in terms of clinical approach, access to care and resource utilization. The aim of the present study was to estimate the cases of dementia amongst immigrant older subjects living in Europe and in each European country. METHODS: The estimated cases of dementia amongst older (i.e. 65+) migrants living in the European Union (EU-28) and European Free Trade Association member states were calculated by multiplying the number of migrants (obtained through the data provided by Eurostat) with the age- and sex-specific prevalence rates (derived by a recent meta-analysis). RESULTS: Overall, 6 507 360 older migrants lived in Europe in 2017. In addition, 1 204 671 migrants were registered in Germany in 2010. Nearly 475 000 dementia cases (329 028 women, 147 410 men) were estimated in this population by applying age- and sex-specific prevalence rates. When considering each European country, the number of estimated cases ranged from 108 (Iceland) to 119 161 (France). In parallel, the proportion of dementia cases occurring in migrants ranged from 0.9% (Czech Republic) to 51.2% (Liechtenstein). CONCLUSIONS: The issue of dementia in migrants and ethnic minorities is emerging but already relevant for European healthcare systems. The magnitude of this phenomenon and its complexities reinforce the need for coordinated initiatives both at a national and continental level. These epidemiological data should ideally be integrated with those coming from 'real world' services in order to better calibrate these actions.

Older HIV-infected adults: complex patients- geriatric syndromes (II).

With the widespread adoption of highly active antiretroviral therapy (HAART), HIV infection starts to be considered one of the many chronic illnesses of advanced age. A growing proportion of the affected patients is presently older than 50. It has been suggested that HIV infection may today represent a model of accelerated and accentuated ageing. The need for a closer collaboration between geriatricians and HIV physicians is being growingly recognised to better address the priorities and needs of HIV patients. The final aim behind the generation of such synergies resides in the design of personalised plans of interventions. These plans should stem from the results of a comprehensive assessment of the individual spanning clinical, environmental, and psychosocial domains. Through the early identification of stressors and risk factors potentially disrupting the homeostatic balance of frail patients (including those living with HIV), it might be possible to protect the "biologically old" (but not necessarily "chronologically old") HIV-infected people from developing detrimental geriatric syndromes. In this article, specific features making the ageing HIV population of special interest for geriatric medicine, and the importance of a multidisciplinary model of care are described. The final objective is to stress how the only way for adequately tackling the multifaceted frailty condition of people with HIV is to implement novel models of care based on the comprehensive geriatric assessment.

Socioeconomic disparities in clinical trials on Alzheimer's disease: a systematic review.

BACKGROUND AND PURPOSE: There is now a wide consensus at recognizing social and economic circumstances as main determinants of an individual's health status. Nevertheless, characteristics relating to socioeconomic status (SES) are poorly described in research reports. The aim of the present review was to verify whether the SES of participants is adequately reported in interventional studies targeting Alzheimer's disease (AD), and to explore the impact of SES proxy measures on the efficacy of the considered medications. METHODS: A systematic review of available randomized controlled trials (RCTs) on the currently marketed drugs for AD (i.e. cholinesterase inhibitors and memantine) was conducted by performing a structured search on PubMed and the Cochrane databases. The following indicators of SES were considered in the retained studies: (i) educational level, (ii) lifetime job category, (iii) income and (iv) wealth. The study quality was assessed using the Cochrane Risk of Bias Tool for Randomized Controlled Trials. RESULTS: A total of 48 articles were finally selected. Overall, only eight RCTs reported data concerning the four considered SES indicators. Indeed, only information pertaining to the educational level of participants was provided. Only one RCT (n = 60) performed ad hoc, secondary analyses accounting for the SES of participating subjects. CONCLUSIONS: The research and clinical relevance of SES has mistakenly been overlooked by the vast majority of RCTs on AD. A greater effort should be made to collect and report data on those SES indicators that may significantly affect the clinical manifestations and trajectories of patients with cognitive disturbances.

Neuropsychological predictors of rapidly progressive Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD), the most common cause of dementia, typically shows a slow clinical progression over time. 'Rapidly progressive' AD, a variant of the disease characterized by an aggressive course, exhibits distinct clinical, biological, and neuropathological features. Here, we investigate neuropsychological predictors of rapid decline in a group of mild patients with AD. METHODS: One hundred fifty-three mild patients with AD admitted to a memory disorder clinic and followed for up to 3 years were included in this study. A comprehensive neuropsychological (NP) battery was performed at the time of enrollment. Patients were defined as 'rapidly progressive' if they exhibited a drop of 6 or more points on the Mini Mental State Examination (MMSE) between two consecutive annual visits. This event defined the main outcome in multiple analyses of variance and Cox proportional hazards models that investigated the impact of NP predictors. Categorical principal component analysis (CATPCA) was also employed in order to delineate clusters of NP tests and to test their effect on the outcome. RESULTS: Of 153 subjects, thirty-seven (24%) were classified as 'rapidly progressive'; those subjects showed younger age of symptoms onset compared to slow decliners (68 vs 71.5 years old). Baseline lower performance on a neuropsychological test of naming predicted a rapid decline over the follow-up (P = 0.001). Three clusters of NP were defined by CATPCA: (i) executive/language, (ii) visuospatial memory, and (iii) verbal memory. The executive/language component predicted a rapid decline over the follow-up (P = 0.016). CONCLUSION: Early executive/language impairment is highly predictive of a rapid progression of AD.

Cognitive frailty: what is still missing?

In recent years, the complex relationship between frailty and cognitive functioning has been increasingly investigated. Accordingly, the concept of "cognitive frailty" was recently proposed to describe a clinical condition characterized by the simultaneous occurrence of both physical frailty and cognitive impairment, in absence of overt dementia diagnosis or underlying neurological conditions. This novel construct has several elements of novelty and may delineate a promising target for preventive and therapeutic actions against age-related conditions. In the present paper we discuss the main issues that are still limiting the clinical and research implementation of the cognitive frailty construct. In particular, a) how to operationalize its definition; b) the supporting epidemiological data; and c) the underlying clinical and biological characteristics constitute points that need to be addressed and clarified.

Binge eating and fast cognitive worsening in an early-onset bvFTD patient carrying C9ORF72 expansion.

An expanded hexanucleotide (GGGGCC) repeat in a non-coding promoter region of open reading frame 72 of chromosome 9 (C9ORF72) has been recently identified as a major cause of familial and sporadic frontotemporal lobar degeneration. We describe the clinical picture of a 64-year-old woman carrying the hexanucleotide repeat expansion, who developed a sporadic early-onset form of behavioral variant frontotemporal dementia characterized by the occurrence of uncommon behavioral manifestations such as binge eating disturbance and by a rapid worsening of cognitive abilities. Our report confirms previous studies asserting that C9ORF72 repeats may sustain heterogeneous clinical syndromes.

Reasoning about Frailty in Neurology: Neurobiological Correlates and Clinical Perspectives.

To date, the frailty syndrome has surprisingly attracted limited attention in the field of neurology and neuroscience. Nevertheless, several concepts closely related to frailty, such as vulnerability, susceptibility, and homeostatic reserves, have been increasingly investigated and documented at level of neuronal cells, brain networks, and functions. Similarly, several aspects commonly assessed in the neurological practice, including cognitive functioning and emotional/affective status, clearly appear to be major determinants of the individual's vulnerability and resiliency to stressors. Therefore, they should be carefully considered in the clinical approach to frail subjects. Moreover, dysfunctions of these domains, if timely detected, may be suitable to be targeted by interventions providing beneficial effects to the overall health status of the individual. In the present article, we discuss the neurobiological processes potentially contributing to frailty. Moreover, we reason about the clinical manifestations allowing the prompt and easy recognition of frail persons in the neurological practice.

Cognitive frailty: rational and definition from an (I.A.N.A./I.A.G.G.) international consensus group.

The frailty syndrome has recently attracted attention of the scientific community and public health organizations as precursor and contributor of age-related conditions (particularly disability) in older persons. In parallel, dementia and cognitive disorders also represent major healthcare and social priorities. Although physical frailty and cognitive impairment have shown to be related in epidemiological studies, their pathophysiological mechanisms have been usually studied separately. An International Consensus Group on "Cognitive Frailty" was organized by the International Academy on Nutrition and Aging (I.A.N.A) and the International Association of Gerontology and Geriatrics (I.A.G.G) on April 16th, 2013 in Toulouse (France). The present report describes the results of the Consensus Group and provides the first definition of a "Cognitive Frailty" condition in older adults. Specific aim of this approach was to facilitate the design of future personalized preventive interventions in older persons. Finally, the Group discussed the use of multidomain interventions focused on the physical, nutritional, cognitive and psychological domains for improving the well-being and quality of life in the elderly. The consensus panel proposed the identification of the so-called "cognitive frailty" as an heterogeneous clinical manifestation characterized by the simultaneous presence of both physical frailty and cognitive impairment. In particular, the key factors defining such a condition include: 1) presence of physical frailty and cognitive impairment (CDR=0.5); and 2) exclusion of concurrent AD dementia or other dementias. Under different circumstances, cognitive frailty may represent a precursor of neurodegenerative processes. A potential for reversibility may also characterize this entity. A psychological component of the condition is evident and concurs at increasing the vulnerability of the individual to stressors.

Efficacy of sertraline in a patient with Neuro-Beçhet's disease.

Behçet's disease (BD) is a heterogeneous multisystem inflammatory disorder of unknown etiology, of which the involvement of the central nervous system is a serious manifestation (Neuro-Behçet's syndrome, NBS). We report a 65-year-old patient who presented with a progressive cognitive impairment and behavioral disturbances (depression and apathy). He fulfilled the International Study Group criteria for BD. Treatment with sertraline was then commenced with an objective improvement of his cognitive and behavioral status. The current report describes a patient with an extensive history of NBS (almost 20 years) and a possible therapeutic option for behavioral impairment.

Restless legs syndrome in a group of patients with Alzheimer's disease.

BACKGROUND: Restless legs syndrome (RLS) is a neurological disorder characterized by the urge to move the legs associated with peculiar unpleasant sensations during periods of rest and inactivity that are relieved by movement. A few studies analyzed RLS in neurodegenerative diseases such as Alzheimer's Disease (AD). The aim of our study was to assess the prevalence and the clinical characteristics of RLS in a cohort of AD patients. METHODS: Three hundred and thirty-nine subjects with a diagnosis of AD were recruited. Cognitive, functional, and neuropsychiatric measures were collected at baseline and six-monthly for a 2-years follow-up RESULTS: Fourteen subjects met the RLS criteria. RLS subjects were more frequently male (p:0,006) and younger than AD subject without RLS (p:0,029). MMSE, ADL and IADL were not significantly different. NPI total scores did not differ significantly, however, AD patients with RLS were found to be more apathetic (p:0,001) than AD subjects without RLS. CONCLUSION: RLS prevalence in our AD cohort was estimated to be about 4%. RLS appeared to be associated with neuropsychiatric symptoms such as apathy. RLS and apathy might share a common pathophysiological basis represented by a dysfunction of the central dopaminergic system.

Frailty and Cognition.

Frailty is a common, heterogeneous, geriatric syndrome associated with adverse health events. Over the last years, a growing debate has emerged concerning the inclusion of cognitive impairment in the definition of frailty. In fact, cognitive impairment has been increasingly recognized as a potential contributor to the clinical vulnerability of older persons. This review presents key studies describing the interrelationships between cognition and frailty; in particular we examine the clinical relevance of cognitive impairment in the determination of the frailty syndrome.