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In recent years, epidemiological, clinical, and biological evidence has drawn the attention on the influence of sex and gender on Alzheimer's 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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Sundowning means the emergence or worsening of neuropsychiatric symptoms (NPS) in the late afternoon or early evening. This syndrome has been recognized since a long time in the field of dementing illnesses and is well known among most of health-care providers involved in the assistance of people with dementia. Indeed, it represents a common manifestation among persons with dementia and is associated with several adverse outcomes (such as institutionalization, faster cognitive worsening, and greater caregiver burden). Its occurrence and phenotypic characteristics may be influenced by diverse neurobiological, psychosocial, and environmental determinants. Moreover, it may pose diagnostic challenges in relation to other common causes of behavioral disruptions. Beside these considerations, this phenomenon has so far drawn limited clinical and scientific interest compared to other specific NPS occurring in dementias, as indicated by the lack of commonly agreed definitions, specific screening/assessment tools, and robust estimates on its prevalence. Accordingly, no randomized controlled trial specifically investigating the effectiveness of pharmacological and non-pharmacological strategies in managing this condition among demented patients has been yet conducted. In the present narrative review, we present and discuss available evidence concerning sundowning occurring in people with dementia. A special focus is given to its definitions, pathophysiological determinants, and clinical relevance, as well as to the clinical and therapeutic approaches required for its management in the daily practice.

Objectives: The issue of subjects with mild cognitive impairment (MCI) reverting to normal cognition (NC) has to date been taken in limited consideration, and no conclusive data are available on the rate of reversion. We aimed at systematically reviewing available longitudinal studies on MCI and meta-analyzing data with the purpose of estimating the proportion of subjects reverting to NC., Design: We performed a systematic bibliographic search on PubMed, the Cochrane Library, and the ISI Web of Science databases. We included in the review all longitudinal studies on MCI published from 1999 up to November 2015. Only studies with a longitudinal design, a follow-up ≥2 years, enrolling subjects with MCI, and reporting the number or the percentage of subjects reverting to NC were included. Data extraction was performed independently by 2 authors. The methodological quality of studies was also assessed by 2 independent authors using the QUIPS tool., Results: Twenty-five studies were included. The quality of evidence was found to be moderate. We observed an overall 18% (95% CI 14-22) reversion rate from MCI to NC. Results from the metaregression showed a significant association between effect size and study setting. In particular, estimates significantly varied according to study setting, with an 8% (95% CI 4-11) reversion rate in clinical-based studies and a 25% (95% CI 19-30) rate in population-based studies. The frequency of reversion from MCI to NC further increased to 26% when considering only studies of better quality. Only a few studies were designed to specifically investigate the reversion from MCI to NC, thus relevant information on this topic was frequently missing., Conclusion: Our data confirm that reversion to normality is a common outcome in subjects with MCI, thus leading to recommend a more balanced view when approaching the construct of MCI both in a clinical and in a research setting., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: Recent evidence suggests that a substantial minority of people clinically diagnosed with probable Alzheimer disease (AD) in fact do not fulfill the neuropathological criteria for the disease. A clinical hallmark of these phenocopies of AD is that these individuals tend to remain cognitively stable for extended periods of time, in contrast to their peers with confirmed AD who show a progressive decline. We aimed to examine the prevalence of patients clinically diagnosed with mild-to-moderate AD who do not experience the expected clinically significant cognitive decline and identify markers easily available in routine medical practice predictive of a stable cognitive prognosis in this population., Design: Data were obtained from two independent, longitudinal, observational multicenter studies in patients with mild-to-moderate AD., Setting: The two studies were the European "Impact of Cholinergic Treatment Use" (ICTUS) and the French "REseau sur la maladie d'Alzheimer FRançais" (REAL.FR)., Participants: We used prospective data of 756 patients enrolled in ICTUS and 340 enrolled in REAL.FR., Measurements: A prediction rule of cognitive decline was derived on ICTUS using classification and regression tree analysis and then cross-validated on REAL.FR. A range of demographic, clinical and cognitive variables were tested as predictor variables., Results: Overall, 27.9% of patients in ICTUS and 20.9% in REAL.FR did not decline over 2 years. We identified optimized cut-points on the verbal memory items of the Alzheimer Disease Assessment Scale-Cognitive Subscale capable of classifying patients at baseline into those who went on to decline and those who remained stable or improved over the duration of the trial., Conclusion: The application of this simple rule would allow the identification of dementia cases where a more detailed differential diagnostic examination (eg, with biomarkers) is warranted. These findings are promising toward the refinement of AD screening in the clinic. For a further optimization of our classification rule, we encourage others to use our methodological approach on other episodic memory assessment tools designed to detect even small cognitive changes in patients with AD., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

The concept of "mild behavioral impairment" (MBI) has been recently introduced and tentatively operationalized. The rationale supporting the need of such novel construct is that neuropsychiatric symptoms (NPS), even when they do not configure major psychiatric disorders, may still constitute early manifestations of neurodegenerative diseases, potentially anticipating the onset of dementia. The conception of MBI as a potential pre-dementia phenotype is surely of interest because posing special attention to neuropsychiatric symptoms and their negative implications. Nevertheless, several issues should be carefully considered in the definition of MBI and are discussed in the present Commentary., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Different rates of cognitive progression have been observed among Alzheimer disease (AD) patients. The present study aimed at evaluating whether the rate of cognitive worsening in AD may be predicted by widely available and easy-to-assess factors., Methods: Mild to moderate AD patients were recruited in the ICTUS study. Multinomial logistic regression analysis was performed to measure the association between several sociodemographic and clinical variables and 3 different rates of cognitive decline defined by modifications (after 1 year of follow-up) of the Mini Mental State Examination (MMSE) score: (1) "slow" progression, as indicated by a decrease in the MMSE score ≤1 point; (2) "intermediate" progression, decrease in the MMSE score between 2 and 5 points; and (3) "rapid" progression, decrease in the MMSE score ≥6 points., Results: A total of 1005 patients were considered for the present analyses. Overall, most of the study participants (52%) exhibited a slow cognitive course. Higher ADAS-Cog scores at baseline were significantly associated with both "intermediate" and "rapid" decline. Conversely, increasing age was negatively associated with "rapid" cognitive worsening., Conclusions: A slow progression of cognitive decline is common among AD patients. The influence of age and baseline cognitive impairment should always be carefully considered when designing AD trials and defining study populations.

Objectives: To determine whether the Frailty Index (FI) was associated with short-term cognitive decline (according to changes in Mini Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores at 1-year follow-up) in individuals with Alzheimer's disease (AD)., Design: Prospective cohort study., Setting: Impact of Cholinergic Treatment USe study., Participants: Individuals with mild-to-moderate AD (N = 973)., Measurements: Severity of dementia was assessed using the Clinical Dementia Rating (CDR). FI was calculated as the ratio of actual to potential deficits (deficits present divided by 30). Linear regression analyses were performed and stratified according to severity of dementia., Results: A 1-unit (0.033 points) increase in FI corresponded to significant and clinically relevant cognitive decline, after adjustments for age, sex, and years of education (0.63-4.63 points on the MMSE, P = .01; 2.87-11.1 points on the ADAS-Cog, P = .001) after 1 year of follow-up. Differences in changes in MMSE and ADAS-Cog scores between nonfrail and frail individuals were 0.67 and 1.6 points, respectively. Although statistically significant, the clinical relevance of this finding remains to be further investigated., Conclusion: The FI may be a promising instrument for the assessment of the vulnerability of individuals with AD. Its implementation in clinical practice may support clinical decisions by identifying individuals at high risk of negative outcomes, specifically, short-term cognitive decline., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Background: The Frailty Index (FI), proposed by Rockwood and Mitniski, measures the deficits accumulation occurring with aging, and can be generated from the results of a comprehensive clinical assessment. Its construct (based on pure arithmetical assumptions) may represent a unique feature for supporting unbiased comparisons among clinical facilities/services., Objective: To propose an example depicting how the FI may support health economic evaluations and provide insights for public health., Design: Observational study., Setting: Nine nursing homes participating in the "Incidence of pNeumonia and related ConseqUences in nursing home Residents" (INCUR) study., Subjects: A sample of 345 older persons living in nursing homes., Methods: A 30-item FI was generated from clinical data retrieved from medical charts. Health care expenditures that occurred over 12 months of follow-up for each participant were obtained from the Caisse Primaire d'Assurance Maladie. Descriptive analyses describing the relationships between the FI of residents with the annual health care expenditures according to nursing home are presented., Results: Mean age of the study sample was 86.0 (SD 7.9) years. The median annual cost per patient was 27,717.75 (interquartile range, IQR 25,917.60-32,118.02) Euros. The median FI was 0.33 (IQR 0.27-0.43). Results are graphically presented to highlight clinical and economic differences across nursing homes, so as to identify potential discrepancies between clinical burden and consumed resources., Conclusions: In this article, an example on how the FI may support health economic analyses and promote an improved allocation of healthcare resources is presented., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

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.

In recent years, "prevention" and "early diagnosis" have been growingly discussed and explored in the field of cognitive disorders. Such increased attention to cognitive disturbances and neurodegenerative conditions may constitute a key step for achieving early/timely diagnosis of dementing illnesses. At the same time, it may generate possible issues (such as a greater proportion of negative diagnostic procedures with potential misuse of resources) that should be acknowledged by health care systems. In this report, we present exploratory analyses aimed at investigating the sociodemographic and clinical changes over time of all the individuals who have been cognitively assessed in a Memory Clinic between 2002 and 2014. Overall, individuals evaluated for cognitive disturbances have gradually become younger, more educated, and less impaired in cognitive and physical functions at their first cognitive assessment. To date, nearly 1 of 4 individuals completing a neuropsychological evaluation has no objective cognitive deficits, thus presenting subjective cognitive complaints. Based on these findings, the development and implementation of strategies for improving the referral to memory clinics is strongly needed., (Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

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.

Purpose of Review: To provide a comprehensive review of the recent literature (published over the last 12 months) exploring the relationship between frailty and cognition., Recent Findings: Fourteen studies were retained for the present review. No randomized controlled trial was found. Overall, the main findings of the selected studies appeared to be mainly confirmatory of the previous evidence. In longitudinal studies, physical frailty was found to predict the incidence of cognitive impairment and dementia. Cross-sectional studies showed that frail individuals have lower cognitive performance compared with nonfrail persons. Interestingly, few studies examined the association between frailty and specific cognitive functions and domains, reporting a significant impairment of attention and executive functions. Finally, we found several studies including cognitive measures in the operational definitions of frailty., Summary: The present findings are suggestive of an almost complete lack of evidence on the addressed topic. In particular, randomized controlled trials are strongly needed in order to gain insights about the possibility of positively affecting the frailty syndrome by acting of cognition and improving cognitive impairment by targeting the physical components of frailty. Moreover, these studies may produce the first evidences about the novel concept of 'cognitive frailty' and its potential for reversibility.

The Italian Dementia National Plan was formulated in October 2014 by the Italian Ministry of Health in close cooperation with the regions, the National Institute of Health and the three major national associations of patients and carers. The main purpose of this strategy was to provide directive indications for promoting and improving interventions in the dementia field, not limiting to specialist and therapeutic actions, but particularly focusing on the support of patients and families throughout the pathways of care. Four main objectives are indicated: 1) promote health- and social-care interventions and policies; 2) create/strengthen the integrated network of services for dementia based on an integrated approach; 3) implement strategies for promoting appropriateness and quality of care; and 4) improve the quality of life of persons with dementia and their families by supporting empowerment and stigma reduction. These objectives and the pertaining actions are described in the present paper.

Several studies have established the sortilin-related receptor gene (SORL1) as a susceptibility locus for Alzheimer's disease (AD). Single nucleotide polymorphisms of SORL1 reported in literature as being associated with AD were investigated in an Italian case-control data set, and their role as a risk factor of conversion to AD was studied in an independent sample of subjects diagnosed with mild cognitive impairment (MCI) at baseline. rs641120, rs2070045, and rs1010159 were genotyped in 734 subjects diagnosed with AD (n = 338) and MCI (n = 181) and in healthy controls (n = 215). Our results confirmed the association between rs641120 and AD (p = 0.01). In the MCI cohort, rs1010159 was associated with conversion to AD (HR = 1.56, p = 0.002). Taken together, these findings confirm that SORL1 is associated with AD and might be a potential tool for identifying MCI subjects at high risk of conversion to AD.

Ginkgo biloba (Gb) is currently the most investigated and adopted herbal remedy for cognitive disorders and Alzheimer's disease (AD). Nevertheless, its efficacy in the prevention and treatment of dementia still remains controversial. Specifically, the added effects of Gb in subjects already receiving "conventional" anti-dementia treatments have been to date very scarcely investigated. We evaluated whether the use of Gb is associated with additional cognitive and functional benefit in AD patients already in treatment with cholinesterase inhibitors (ChEIs). Data are from mild to moderate AD patients under ChEI treatment recruited in the Impact of Cholinergic Treatment USe (ICTUS) study. Mixed model analyses were performed to measure six-monthly modifications in the Mini Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score, and the Activities of Daily Living (ADL) scale over a follow-up of 1 year according to the additional Gb supplementation. A total of 828 subjects were considered for the present analyses. Significantly different modifications at the MMSE score over the 12-month follow-up were reported between patients on combined therapy compared to those only taking ChEIs. On the contrary, the modification of the ADAS-Cog score between the two groups did not show statistically significant differences, although similar trends were noticed. No significant modifications of the two adopted outcome measures were observed at the mid-term 6-month evaluation. The modifications over time of the ADL score did not show statistically significant differences between the two groups of interest. Our findings suggest that Gb may provide some added cognitive benefits in AD patients already under ChEIs treatment. The clinical meaningfulness of such effects remains to be confirmed and clarified., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Familial Alzheimer's 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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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.

Objective: Behavioral and psychological symptoms of dementia represent common clinical features of dementias, contributing to the heterogeneous phenotypic expression of Alzheimer's disease (AD). During the last two decades, several studies explored the possible presence of neuropsychiatric subsyndromes in dementia by examining the internal structure of the Neuropsychiatric Inventory (NPI). The aim of the present review is to present available evidence coming from studies adopting factor analysis to explore the NPI and describe neuropsychiatric clusters of symptoms in AD., Design: A systematic review of literature was performed concerning available studies describing neuropsychiatric subsyndromes in AD by adopting the NPI., Results: Overall, our analysis showed a relatively low concordance among available evidence for what concerns the definition and composition of NPI clusters, possibly due (at least in part) to the heterogeneity of the sample populations recruited in the studies. However, we also observed some consistent associations of specific symptoms across studies, defining potential subsyndromes in AD. More consistent results were obtained by studies evaluating the 10-item version of the NPI rather than the more recent 12-item one., Conclusions: This review represents the first attempt to systematically evaluate evidence coming from factor analyses exploring the internal structure of the NPI in order to facilitate the identification of neuropsychiatric syndromes in AD patients. The NPI may support the definition of behavioral subsyndromes in AD. The evaluation of neuropsychiatric subsyndromes should always take into account the main potential confounders, such as age, severity of disease, and concomitant pharmacological treatment., (Copyright © 2012 John Wiley & Sons, Ltd.)

Inappropriate sexual behaviors (ISB) represent uncommon and often misdiagnosed clinical disorders among patients with Alzheimer disease. So far, no randomized clinical trials regarding the treatment of ISB in demented people have been conducted, but available data from case series and isolated case reports suggest the efficacy of selective serotonin reuptake inhibitors (SSRIs), antipsychotics, antiandrogens, and H2-receptor antagonists. Controversial data exist on the therapeutic influence of cholinesterase inhibitors on sexual disorders. In the present article, we describe the case of an Alzheimer disease patient presenting hypersexuality, successfully treated with rivastigmine. Thus, we perform a revision of the existing literature regarding the therapeutical effect of cholinesterase inhibitors in the treatment of ISB.

Behavioral and psychological symptoms of dementia (BPSD) represent common manifestations among patients affected by Alzheimer's disease (AD). Some reports have recently classified BPSD into specific clusters/subsyndromes exploring the internal structure of the Neuropsychiatric Inventory (NPI). We evaluated whether specific behavioral subsyndromes are associated with worsening cognitive function. Mild to moderate AD patients were recruited from the cohort of the Impact of Cholinergic Treatment USe (ICTUS) study. Neuropsychiatric symptoms were classified in three subsyndromes, identified at baseline, grouping different combinations of NPI items: (1) "psychotic" ("delusions" and/or "hallucinations"); (2) "affective" ("agitation" and/or "depression" and/or "anxiety" and/or "irritability"); and (3) "behavioral" ("euphoria" and/or "apathy" and/or "disinhibition" and/or "aberrant motor behavior"). Mixed model analyses were performed to measure six-monthly changes in the ADAS-Cog score over a follow-up of 2 years, according to these subsyndromes. All analyses were stratified according to AD severity as defined by the Clinical Dementia Rating (CDR). A total of 1,375 AD subjects were recruited. No NPI cluster was found to significantly (p < 0.05) affect the rate of cognitive decline across the 3 CDR classes. Our results suggest that the cognitive course of AD is not substantially influenced by the presence of specific neuropsychiatric phenotypes. Further studies are needed to extend the present findings and identify possible biological and clinical bases for behavioral subsyndromes.

Lymphomatosis cerebri (LC) is a rare form of primary central nervous system lymphoma; we report a case of LC mainly involving the brainstem and cerebellum. This diagnosis should be considered in patients presenting with diffuse white matter disease, and a subacute clinical history of cognitive deficits, ataxic gait, and personality changes. We present our findings along with a review of the neuroradiological literature., (Copyright © 2010 by the American Society of Neuroimaging.)