Marco Canevelli

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.

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.

Sex and gender differences in the treatment of Alzheimer’s disease: A systematic review of randomized controlled trials

Graphical abstract Figure. No caption available. ABSTRACT In recent years, epidemiological, clinical, and biological evidence has drawn the attention on the influence of sex and gender on Alzheimers disease (AD). Nevertheless, not enough attention has been paid to their impact on treatment outcomes. The present study is aimed at systematically retrieve, review and discuss data coming from available randomized placebo‐controlled trials (RCTs) on currently marketed treatments for AD (i.e., cholinesterase inhibitors [ChEIs] and memantine) in order to describe possible sex and gender differences in their efficacy, safety and tolerability. A systematic review of literature was performed. None of the retrieved studies reported data on the efficacy, safety and tolerability of considered medications separately in male and female patients with AD. We thus analyzed 48 excluded studies of potential interest, that is, almost all of the currently available trials on the four considered drugs. Nearly all the considered RCTs recruited a larger number of female participants to mirror the sexually unbalanced prevalence of AD. Only two studies took into account the potential influence of sex and gender on treatment efficacy, reporting no significant differences between men and women. None of the studies investigated potential sex and gender differences in the safety and tolerability of the four considered treatments. The existence of sex and gender differences in the efficacy and tolerability of ChEIs and memantine in AD has, to date, drawn limited to no attention. However, a considerable amount of data, with an adequate representativeness in terms of sex/gender distribution, seem to be already available for dedicated analyses on this topic. A greater effort should be made to collect and report data on those factors interacting with sex and gender that may significantly influence clinical manifestations, outcomes, and trajectories over time of AD patients.

Familial Alzheimer's disease sustained by presenilin 2 mutations: Systematic review of literature and genotype–phenotype correlation

Familial Alzheimers disease (FAD), despite representing a rare condition, is attracting a growing interest in the scientific community. Improved phenotyping of FAD cases may have a relevant impact both in clinical and research contexts. We performed a systematic review of studies describing the phenotypic features of FAD cases sustained by PSEN2 mutations, the less common cause of monogenic AD. Special attention was given to the clinical manifestations as well as to the main findings coming from the most commonly and widely adopted diagnostic procedures. Basing on the collected data, we also attempted to conduct a genotype-phenotype correlation analysis. Overall, the mutations involving the PSEN2 gene represent an extremely rare cause of FAD, having been reported to date in less than 200 cases. They are mainly associated, despite some peculiar and heterogeneous features, to a typical AD phenotype. Nevertheless, the frequent occurrence of psychotic symptoms may represent a potential distinctive element. The scarcity of available phenotypic descriptions strongly limits the implementation of genotype-phenotype correlations.

Serotonin toxicity: a short review of the literature and two case reports involving Citalopram

The serotonin toxicity (ST) is a potentially life-threatening adverse drug reaction results from therapeutic drug use, intentional self-poisoning, or inadvertent interactions between drugs. ST can be caused by a single or a combination of drugs with serotonergic activity due to excessive serotonergic agonism on central nervous system and peripheral serotonergic receptors (monoamine oxidase inhibitors, tricyclic antidepressants, SSRIs, opiate analgesics, over-the-counter cough medicines, antibiotics, weight-reduction agents, antiemetics, antimigraine agents, drugs of abuse, H2-antagonist and herbal products). The serotonin toxicity is often described as a clinical triad of mental-status changes (agitation and excitement with confusion), autonomic hyperactivity (diaphoresis, fever, tachycardia, and tachypnea), neuromuscular abnormalities (tremor, clonus, myoclonus, and hyperreflexia) and, in the advanced stage, spasticity; not all of these findings are consistently present. In this article, we describe two cases of ST due to interaction between Citalopram and two CYP2D6 inhibitors: Cimetidine and Topiramate and their clinical resolution after treatment discontinuation.

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 Alzheimers 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

Nutrition and Dementia: Evidence for Preventive Approaches?

In recent years, the possibility of favorably influencing the cognitive trajectory through promotion of lifestyle modifications has been increasingly investigated. In particular, the relationship between nutritional habits and cognitive health has attracted special attention. The present review is designed to retrieve and discuss recent evidence (published over the last 3 years) coming from randomized controlled trials (RCTs) investigating the efficacy of nutritional interventions aimed at improving cognitive functioning and/or preventing cognitive decline in non-demented older individuals. A systematic review of literature was conducted, leading to the identification of 11 studies of interest. Overall, most of the nutritional interventions tested by the selected RCTs were found to produce statistically significant cognitive benefits (defined as improved neuropsychological test scores). Nevertheless, the clinical meaningfulness of such findings was not adequately discussed and appears controversial. In parallel, only 2 studies investigated between-group differences concerning incident dementia and mild cognitive impairment cases, reporting conflicting results. Results of the present review suggest that several dietary patterns and nutritional components may constitute promising strategies in postponing, slowing, and preventing cognitive decline. However, supporting evidence is overall weak and further studies are needed.

From Evidence to Action: Promoting a Multidimensional Approach to Mild Cognitive Impairment.

To the Editor: Mild cognitive impairment (MCI) is commonly indicated as an intermediate state between normal cognitive functioning and dementia, and represents the object of growing scientific and clinical interest.1 This entity was originally proposed for research purposes, in particular for allowing the detection of early pathophysiological modifications responsible for subsequent dementia. It has rapidly been acquiring clinical value and is today widely regarded as a specific nosographic entity (as also confirmed by the formulation of specific diagnostic criteria2). Nevertheless, despite robust supporting evidence, some key aspects of this construct are frequently neglected, thus resulting in a biased and unbalanced use of it. To date, particularly in neurology settings, MCI is largely considered as the manifestation of an incipient neurodegenerative process (ie, early stage of Alzheimer disease or another neurological disorder). Accordingly, major efforts have been devoted to the identification of clinical and biological factors predictive of its progression to dementia.3,4 Adopting a broader viewpoint, MCI may also represent the “cognitive” expression of concurrent and underlying pathological conditions not merely confined to the nervous system. Evidence clearly shows that nutritional deficiencies, affective disturbances, physical frailty, sleep disorders, and multiple medical conditions can directly or indirectly sustain an objective decline of cognitive performance.1,5 This means that MCI should be considered the manifestation of a global homeostatic disruption and, as such, approached using a broader, more flexible, and holistic assessment. Such framework may easily find support in the proven effectiveness of interventions apparently targeting specific domains of the health status (eg, physical activity, cardiovascular care, social engagement), but capable of exerting more systemic benefits to the individual, including to his or her cognitive function.1 Describing MCI as an age-related pathological condition6 implies the necessity of abandoning the traditional approach simply limiting it to a synonym of incipient neurodegeneration. The onset of cognitive impairment should be multidimensionally explored so as to identify underlying conditions explaining the cognitive disturbances and serve as targets for person-tailored preventive/ therapeutic interventions. The cognitive impairment sustained by non-neurodegenerative conditions may likely benefit from different interventions compared with the one determined by neurodegeneration.7 This means improving the personalization of care and promoting the design of more effective interventions. It is noteworthy that better differentiating the etiopathogenesis of the MCI will in parallel allow to potentially increase the effect size of the available specific treatments for individuals with clear neurodegenerative conditions. Substantial evidence shows that individuals with MCI present an increased risk of incident dementia. However, most affected individuals do not experience significant cognitive worsening over time (even over the long term).8 Moreover, a sizeable proportion of cases may revert back to normal cognition.9 The bidirectional modifications of MCI should induce a careful thinking about the risk of incorrect diagnosis of cognitive impairment in individuals with normal cognition and the often underestimated reversibility of MCI. The still too limited study of characteristics explaining the reversion from MCI to normal cognition may have important practical implications. Improved identification of individuals with a favorable cognitive trajectory will allow better allocation of health care resources and avoid misdiagnoses in individuals with MCI. It is noteworthy that by enlarging the target population from patients with dementia to individuals with MCI, research is surely going toward early phases of neurodegenerative diseases but is also exposed to the risk of a higher number of false-positive cases. In fact, the larger the population of interest, the more heterogeneous it will be. This means that clinical research in individuals with MCI may not necessarily facilitate the identification of clear pathophysiological mechanisms as the basis of the neurodegenerative conditions. This paradigm is valid only if a rigid and clear selection of individuals with MCI is made up front so as to limit the recruitment to those who will most likely develop dementia in the future. Finally, the ethical aspects of an MCI diagnosis should be always clearly present to clinicians because potentially affecting the psychological well-being of the patient and his or her proxies. In fact, an individual receiving an MCI diagnosis may easily incur in a number of potentially harmful consequences, such as discrimination, stigmatization, and overmedicalization.10 In conclusion, MCI should not be primarily/exclusively thought of as the prelude to unavoidable future dementia, but regarded as a condition presenting equal (if not higher) potential for being reversed to normality. MCI should be multidimensionally approached because it represents a heterogeneous risk factor, and not be considered as a disease. A more cautious and conservative approach will probably minimize the negative consequences of “labeling” an individual as affected by an undefined condition, and promote the personalization of care.

Cognitive interventions targeting subjective cognitive complaints.

Subjective cognitive complaints (SCCs) are being increasingly recognized as a preclinical phase of dementia. Thus, SCCs may represent a “promising” stage for planning and implementing preventive interventions aimed at reducing the incidence of cognitive disorders. The aim of the present study is to present and discuss the available evidence coming from clinical trials adopting cognitive interventions in individuals with SCCs. A systematic review of literature was conducted to evaluate the available trials testing nonpharmacological cognitive interventions for the prevention of dementia in subjects with SCCs. Six studies were included in the present study. Overall, most interventions showed to objectively improve cognitive performance in subjects with SCCs. A relevant heterogeneity was found concerning their characteristics and feasibility. Conversely, there is a current lack of evidence in the literature about the efficacy of nonpharmacological cognitive interventions for preventing dementia or cognitive impairment.

Issues about the use of subjective cognitive decline in Alzheimer's disease research

Recently, Jessen et al. [1] have described the conceptual framework for “subjective cognitive decline” (SCD) in Alzheimer’s disease (AD) research. SCD has been indicated as a possible risk factor for incident cognitive impairment and dementia [2], and pathophysiological commonalities have been reported between subjects with SCD and AD [3]. The hypothesis that SCD might represent a preliminary stage of the dementia cascade has already brought to the development of specific preventive trials targeting individuals with subjective cognitive complaints [4]. Nevertheless, to date, the study of SCD is hampered by the lack of a shared and agreed terminology. Thus, SCD has so far been differently defined, screened, and measured [5]. By proposing a new lexicon for SCD, Jessen et al. [1] address an important gap in the field. The authors proposed the core criteria for defining SCD and recommendations for its adoption as a preclinical model of AD in research. The article indeed poses itself as a possible cornerstone for future research in the field. However, we would like to point out some issues that we believe should have been better considered and discussed by the authors. The course of SCD over time is quite unstable (and often unpredictable), so that it can progress toward overt cognitive impairment and revert to a subjective experience of normal mental efficiency [6,7]. Interestingly, despite being commonly described, the reversion to normal cognition has also been frequently neglected in other predementia conditions, including mild cognitive impairment (MCI) [8]. Moreover, because all the assessment tools we use in clinics and research for objectively defining cognitive abnormalities present methodological and accuracy limitations, the risk of misclassification across these conditions is present and enhanced by the limited knowledge about them. The possible inversion of the SCD trajectory can be easily explained when the condition is sustained/influenced by temporary reversible clinical conditions (e.g., pain, depressive symptoms, fatigue). To operationalize the novel construct, Jessen et al. proposed to exclude any “psychiatric