Frailty and behavioral and psychological symptoms of dementia: a single center study

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During the dementia time-course, Behavioral and Psychological Symptoms of Dementia (BPSD) may arise, greatly impacting on the management and outcomes of the disease. Considering that dementia mainly affects the older population, the possible link to frailty should be considered. Methods Aim of this single centre, longitudinal study was to evaluate the correlation between frailty and BPSD in a population of older patients with dementia. BPSD were classified in three clusters: “mood/apathy” (depression, apathy, sleep disturbances, appetite disturbances), “psychosis” (delusions, hallucinations and anxiety) and “hyperactivity” (agitation, elation, motor aberrant behavior, irritability, disinhibition). Using the Clinical Frailty Scale (CFS), patients were categorized as “severely frail”, “mild/moderately frail” and “robust” (CFS ≥ 7, 4–6 and ≤ 3, respectively). Results Two-hundreds and nine patients (mean age 83.24 ± 4.98 years) with a clinical diagnosis of dementia were enrolled. Among the “severely frail” the percentage of BPSD was higher compared to the other two groups in the three clusters. A positive correlation between frailty and “hyperactivity” cluster, at baseline and follow up visits (p < 0.001, p = 0.022, p = 0.028 respectively) was found. This result was confirmed with the network analysis, showing that frailty, expressed by CFS, relates to agitation and motor aberrant activity. Conclusions Frailty may help identifying patients at the highest risk for developing BPDS thus, targeting intervention in the earliest phases of the disease. In-depth studies in larger cohorts of patients are needed to confirm and extend these results. frailty dementia behavioural and psychological symptoms in dementia (BPSD) hyperactivity Figures Figure 1 Background Dementia is a clinical syndrome characterized by progressive decline in multiple cognitive domains and loss of independence in activities of daily living; affecting 47 million people worldwide, dementia is a growing public health issue with considerable economic impact, with ageing as a major risk factor, as the prevalence of dementia almost doubles every five years after 65 years of age [ 1 , 2 ]. Alongside the cognitive symptoms, alterations in personality and behavioral changes, such as agitation, apathy, aggression, psychosis, hallucinations and delusions, may arise. Behavioral and Psychological Symptoms of Dementia (BPSD) may be among the earliest signs of cognitive decline [ 3 , 4 ]. BPSD clinical presentation varies greatly among individuals, having unpredictable courses, and could fluctuate in intensity and switch to one another over time; thus, considerable distress to both patients and caregivers is often reported [ 5 ]. BPSD are associated with several negative outcomes, such as faster cognitive decline and progression to more severe stages of dementia, loss of independence, increased risk for secondary complications such as falls and fractures, representing the leading reason for higher hospitalization rates and early institutionalization [ 6 ]. Neuropsychiatric symptoms may be present very early in the time course of cognitive impairment, some of them, like depression, may be present very early, sometimes in the MCI phase (Mild Cognitive Impairment), with a prevalence ranging from 25–40% in clinical studies [ 7 ]. BPSD can be grouped into distinct clusters, according to similar features, and few possible classification has been hypothesized [ 8 – 10 ]. The existence of behavioral subsyndromes, with each group of symptoms reflecting a different prevalence, timeline, biological and psychosocial factors, can help identifying the possible correlations between BPSD and clinical variables, outlining specific interventions targeting BPSD subsyndromes rather than individual symptoms [ 8 ]. Considering that dementia mainly affect older people, it would be interesting to evaluate the possible link to other geriatric syndromes, and in particular to frailty. Frailty is defined as an aging-related syndrome, characterized by increased vulnerability to adverse events, with reduced tolerance to medical and surgical interventions [ 11 ]. Frail older patients often present with an increased burden of symptoms and are predisposed to negative health outcomes, such as falls, fractures, hospitalization, disability, poor quality of life, with higher risk of institutionalization. Current evidence in the literature has shown a strong correlation between frailty and cognitive disorders, while literature about the possible correlation between BPSD and frailty is scarce. Aim of the current study was to evaluate the possible correlation between frailty and BPSD, clustered, according to Aalten et al, as “mood apathy” (depression, apathy, sleep disturbances, appetite disturbances), “psychosis” (delusions, hallucinations and anxiety) and “hyperactivity” (agitation, elation, motor aberrant behavior, irritability, disinhibition) [ 8 ], in a population of older patients with dementia, at baseline and over time across a year follow-up (6 and 12 months). Moreover, the direction strength of the potential association between single BPSD and frailty was evaluated. Materials and methods This is a longitudinal, single center study. Patients referred to our Memory Clinic aged 65 years old and more, presenting with cognitive complaint were consecutively enrolled. The study protocol complied with the Declaration of Helsinki and was approved by the local Ethic Committee (CEAVNO, approval number 22187). Informed consent was acquired from patients or next of kin, as per protocol. Demographic characteristics and clinical history were obtained, along with Comprehensive Geriatric Assessment (CGA) and physical and functional examination. CGA was performed by using the following scales: Cumulative Illness Rating Scale (CIRS-c) [ 12 ], Basic (ADL) and Instrumental (IADL) Activities of Daily Living [ 13 ], Mini Mental State Examination (MMSE) [ 14 ]. Frailty was assessed using the visual analogic scale Clinical Frailty Scale (CFS) [ 15 ]. Patients were further categorized as “severely frail”, “mild/moderately frail” and “robust” on the basis of CFS score (CFS respectively, ≥ 7, 4–6 and ≤ 3). The NPI scale was used in order to assess the presence and severity of neuropsychiatric symptoms; information for the NPI was obtained from the caregiver. According to Aalten et al . BPSD were classified in three different clusters: “mood/apathy”, “psychosis” and “hyperactivity” [ 8 ]. Patients were assigned to a cluster according to the presence of at least one symptom reported at the NPI scale. Patients were evaluated at baseline and 6 and 12 months follow up visits; we have allowed a time window between 5 and 7 months for the first follow up, and 11–13 months for the second visit. Statistical analysis Statistical analysis was performed by using SPSS 21.0 statistical software package (SPSS Inc., Chicago, IL). Demographic and clinical characteristics among groups were compared using Analysis of variance (ANOVA) for continuous normally distributed variables and Chi-square test (χ2) for categorical or dichotomous variables. Continuous variables were expressed as mean ± standard deviation, ordinal variables as median and interquartile range, and categorical variables as percentage. One-way repeated measures analysis of variance (ANOVA) with Bonferroni correction was used to compares means for continuous variables (ADL, IADL, MMSE, CFS) at 6 and 12 months follow up visits. We used linear regression to estimate the association between the number of symptoms of all the three BPSD clusters and CFS score; logistic regression was used to analyze the relationship between categorical variables, such as the presence of one or more symptoms of a particular cluster and multiple influencing factors, including ADL, IADL, CFS, MMSE, age. Stepwise regression was performed, considering age, CFS, ADL, IADL, MMSE and CIRS scores as independent variables, to evaluate the possible contribution of single factors to the correlation with BPSD Statistical significance was assigned for p < 0.05. We also developed a network analysis with the secondary endpoint of identify the most influent symptom in relation to the frailty degree of our population. The nodes represent various variables, including different type of BPSD and other factors like CFS and CIRS. The edge may be positive (e.g. positive correlation) or negative (e.g. negative correlation) and the polarity of the relationship is represented graphically using different colored lines, blue for positive relationships and red for negatives relationships. Varying the thickness and color density of the edges we underlined the strength of the relationships. Results A total of 209 patients referred to our Outpatient clinic from 2018 to 2021 with a clinical diagnosis of dementia (71.3% women; mean age = 83.24±4.98 years) were enrolled. The main demographic and clinical characteristics of the studied subjects are summarized in Table 1. Table 1: characteristics of the study population Baseline 209 6 months follow up 146 12 months follow up 98 Age (mean±SD) 83.24±4.99 Gender F (%) 71.3 CIRS score (mean±SD) 9.26±5.4 CIRS-c (mean±SD) 1.35±1.5 CIRS-s (mean±SD) 1.67±0.8 CFS (median, IQR) 5 (1) *,# 6 (1.25) 6 (1.5) ADL (median, IQR) 5 (3) *,#,^ 4(3.25) 3(3) IADL (median, IQR) 3(4) *,#,^ 2(4) 1(3) MMSE (mean ± SD) 19.08±5.0 *,#,^ 17.71±5.8 17.02±5.8 NPI (frequency x severity) (mean±SD) 6.63±6.6 7.53±7.4 7.85±7.7 NPI distress (mean ± SD) 3.98±3.6 4.83±4.4 4.92±4.3 * p<0.05 between b and 6 months # p<0.05 between b and 12 months ^ p<0.05 between 6m and 12 months Abbreviations. CIRS: Cumulative Illness Rating Scale; CFS: clinical frailty scale; ADL: activities of daily living; IADL: instrumental activities of daily living; MMSE: mini mental state examination; NPI: neuropsychiatric inventory; IQR: interquartile range. At baseline, the study cohort showed a low burden of comorbidity (mean CIRS-C score 1.35±1.5), a mild degree of frailty with a need for help in high order IADLs [CFS 5 (IQR 1), ADL 5 (IQR 3), IADL 3 (IQR 4)], and moderate cognitive decline (MMSE score 19.08±5.0).NPI scale for the assessment of BPSD showed a moderate degree of severity of symptoms and caregiver distress (NPI axb 6.63±6.6, NPI distress 3.98±3.6). The repeated measure ANOVA conducted over the three timepoints showed that each pairwise difference was significant. The results of the ANOVA indicated a significant time effect on functional status, with worsening of ADL and IADL over time [ADL Wilks’ Lambda=0.744, F(2.80)=13.75, p<0.001, η 2 =0.256, IADL Wilks’ Lambda=0.71, F(2.80)=16.3, p<0.001, η 2 =0.29, respectively]. Likewise, there was a significant progression of cognitive impairment as measured with MMSE and a significant worsening of frailty by CFS [MMSE Wilks’ Lambda=0.751, F(2,73)=12.11, p<0.001, η 2 =0.249, CFS Wilks’ Lambda=0.749, F(2.79)=13.224, p<0.001, η 2 =0.241]. In particular, ADL significantly worsened between baseline and 6 months follow up (median values 5±3 and 4±3.2 respectively, p=0.005), between 6 months and 12 months (median values 4±3 and 3, respectively p<0.001) and between baseline and 12 months (p<0.001). IADL worsening was significant between baseline and 6 months follow-up (median values 3±4 and 2±4 respectively, p=0.002), between 6 and 12 months (median values 2±4 and 1±3 respectively, p<0.001) and baseline and 12 months (p<0.001). The same trend was observed for the MMSE score, with a progressive significant worsening baseline and 6 months (mean values 19.08±5 and 17.71±5.8 respectively, p=0.041), between 6 and 12 months (mean values 17.71±5.8 and 17.07±5.8 respectively, p<0.01) and between baseline and 12 months as well. The worsening of CFS was significant between baseline and 6 and 12 months follow up (median value 5±1 and 6±1.25 respectively, p<0.001), and between 6 and 12 months (median value 6±1.25 and 6±1.5, respectively, p=0.025). The most represented group was the mild/moderately frail one (n=155); lower numbers were seen in the robust (n=18) and severely frail (n=36) ones. Within the mild/moderately frail subgroup, about 55.5% of the patients showed at least one symptom of the "mood/apathy" cluster at baseline and this percentage remained consistent throughout the follow-up period. Among the severely frail subgroup, this percentage was significantly higher, with 69.4% (p=0.04) exhibiting at least one symptom of this cluster at baseline. Similarly, the percentage of patients with symptoms in the "psychosis" and "hyperactivity" clusters remained high among the severely frail patients as opposed to the mild-moderately frail group. The results are shown in Appendix. At linear regression, the number of symptoms of the hyperactivity cluster correlated with the degree of frailty, at baseline and at 6 months and 12 months follow up (p<0.001, p=0.022, p=0.028 respectively). Conversely, no association was observed with both the mood/apathy and the psycosis clusters. To evaluate the possible contribution of single factors to the correlation with BPSD clusters, a stepwise regression was performed, considering age, CFS, ADL, IADL, MMSE and CIRS scores as independent variables. At baseline the loss of independence in IADL resulted the independent risk factor for the “hyperactivity” cluster (p<0.001) and, the burden of comorbidity evaluated by CIRS-C score for the “psychosis” cluster, (p=0.016). While the burden of comorbidity (CIRS-C), the degree of frailty (CFS) and the age concurred as significant risk factors for symptoms of the “mood/apathy” cluster, although with different strength (p=0.008, p= 0.004 and p<0.001 respectively) (Table 2). Table 2: Stepwise Regression for the hyperactivity cluster Unstandardized Coefficients Standardized Coefficients Beta t Sign. B Standard error 1 (Costant) .571 .050 11.492 <.001 IADL_b -.058 .013 -.305 -4.612 <.001 Dependent variable: HYPERACTIVITY Abbreviation: IADL_b: instrumental activities of daily living_baseline In order to better understand the complex pattern of relationships between the different factors, we performed a network analysis. In our model represented in Figure 1not all nodes are equally important in determining the network’s structure; clustering of nodes that are highly interconnected among themselves and poorly connected with nodes outside the cluster can be identified. The degree of frailty, expressed by CFS, relates to behavioral and psychological symptoms of the hyperactivity cluster, such as agitation and motor aberrant activity; the relationship is still positive although not so strong with other symptoms like apathy and hallucinations. The clustering of nodes also reflects the clustering of different BPSD in the three subgroups we identified: psychosis, mood/apathy and hyperactivity clusters. Logistic regression showed that at baseline, the reduced ability to perform instrumental activities of daily living (IADL) was associated with symptoms of the “hyperactivity” cluster (p=0.022); this finding was confirmed at 6 months follow up (p=0.003), while at 12 months a strong association emerged with CFS (p=0.008). A significant association between the presence of one of more symptoms of the “mood/apathy” cluster with both the degree of frailty (CFS) and the age (p=0.019, p=0.032, respectively) was obtained at baseline. Discussion The aim of our study was to evaluate the impact of frailty, on the presence, onset and progression of specific clusters of BPSD in older patients referred to our Memory Clinic, at baseline and during follow up. Current evidence in the literature has shown a strong correlation between frailty and cognitive disorders, including mild cognitive impairment and dementia, suggesting that cognition and frailty may interact within a cycle of age-related decline [16-18]. The degree of frailty could contribute to cognitive decline, with frail older adults at higher risk of developing dementia compared to robust ones [19-22]. Despite the ample literature existing on the association between frailty and dementia, to the best of our knowledge, scanty data are available on the correlation between the degree of frailty and BPSD clusters. Sugimoto et al. evaluated the association between physical frailty and BPSD in a cohort of patients with AD (Alzheimer Disease), with physical frailty calculated with 38 items Frailty Index (FI). The results of the study showed that presence of physical frailty and pre-frailty increased the BPSD burden in patients with AD [23]. That is confirmed in our cohort, where the cluster of subjects with higher comorbidity burden and lower cognitive and physical performance showed higher prevalence of psychiatric symptoms. Among our cohort of older patients, the prevalence of neuropsychiatric symptoms was different among the “robust”, “mild/moderate frail” and “severely frail” subgroups. Even though the most represented group was the “mild/moderately frail” one, the percentage of patients presenting with at least one symptom per cluster was higher in the “severely frail” compared to the other groups. In particular, almost two third of patients of the “severely frail” subgroup showed neuropsychiatric symptoms of the “mood/apathy” cluster at baseline, remaining substantially stable during follow-up. Similarly to what observed for the “mood/apathy” cluster, the prevalence of “severely frail” patients with neuropsychiatric symptoms of the “psychosis” and “hyperactivity” clusters was always higher compared to patients of the “mild/moderate frail” subgroup, suggesting that the degree of frailty could be associated to the burden of BPSD symptoms. Accordingly, as shown in the network analysis graph, the degree of frailty at baseline is positively correlated to agitation and motor aberrant activity, both belonging to the hyperactivity cluster. However, the contributing role of BPSD to frailty and, possibly, the reverse is yet to be determined. Consistently, regression analysis confirmed that reduced score in the IADL appears to be correlated with symptoms of the hyperactivity cluster, which may suggest either that the loss in higher functions could be a trigger for aberrant behaviors in subjects with cognitive impairment, or that the presence of hyperactivity symptoms may affect the ability of efficiently perform complex activities of daily living. It also should be acknowledged that this study has been conducted in a time window comprehensive of the pandemic crisis, when social interactions were forbidden, or at least limited. Thus, physical or behavioral worsening might partially be a consequence of the social situation, and studies on a larger scale would be desirable. Although literature about the possible correlation between BPSD and frailty is scarce, a lot has been written about the association between frailty and delirium. Postoperative Cognitive Dysfunction (POCD) and delirium (POD) are the most common perioperative cognitive complications in older patients undergoing different surgical procedures, such as spine surgery [24] or major noncardiac surgery [25]. A meta-analysis by Zhang et al. of a total of 30 independent studies from 9 countries, consisting of 217623 hospitalized patients (medical, surgical, emergency and critical illness patients), showed an increased risk of delirium in frail patients compared to those not frail [26]. Among the different BPSD clusters, hyperactivity shares some features with delirium, in particular with hyperkinetic and mixed delirium. Considering that delirium usually presents with symptoms that are common to the "hyperactivity" cluster, the association between this cluster and frailty do not surprise. Moreover, it should be considered the possibility that some diagnosis of delirium, especially if and when lasting for long time after discharge, could rather be a symptom of BPSD and a sign of dementia, supporting the need of cognitive follow up of all patients developing in-hospital delirium. The results of our research also suggest the usefulness of an in-depth study in a larger cohort of patients with cognitive impairment and BPSD. A strength of our study is that the cohort of patients could be considered representative of the general oldest population, since our sample is composed by patients referred from the community for cognitive complaint. Even though the results of the study are promising and interesting, we have to acknowledge few limitations. First of all, the patients enrolled have a clinical diagnosis of Alzheimer’s Disease or mixed dementia, based on clinical criteria and structural imaging, but without the biomarkers, therefore we could not exclude some misdiagnosis. However, patients with highly suspicious frontotemporal dementia, Lewy body dementia, Parkinson’s disease dementia or post-stroke dementia were not included in the dataset. Moreover, the patients presenting BPSD were a small number, and a wider cohort would have been more informative, especially enrolling more patients “robust” and “severely frail”. We also acknowledge that 1-year follow up might not be sufficient to draw conclusions about the progression of two chronic and progressive diseases like dementia and frailty. However, being literature about this topic still scarce, we considered an initial short-term evaluation a possible starting point for further and more powered studies. A further analysis evaluating not just the single cluster, but also the combination of them would certainly be more informative and representative of the general population, but the present cohort is not sufficiently large for further division in subgroups. Conclusions The purpose of the current study was to determine if the presence of physical frailty, as determined by the CFS, could represent a risk factor for the development and progression of BPSD in older patients with AD. One of the most significant findings emerged from this study is the association between frailty and the number of neuropsychiatric symptoms of the “hyperactivity” cluster; however, whether the loss of independence is a possible cause of frailty or viceversa is still to be determined. The results of this study suggest that the assessment of frailty may help identifying patients at risk of developing behavioral and psychological symptoms of dementia, and could provide the clinicians with a time-window to target intervention in the earliest phases of both frail condition and BPSD. This is of crucial importance, especially because an early intervention may benefit from non-pharmacological approaches, saving patients from prescription of antipsychotics drugs which are linked to several adverse events. Given the importance of frailty assessment, especially in the oldest population, a standardized approach to physical frailty evaluation in future clinical studies is highly desirable and would provide clinicians with simple and highly efficient tools for the patients’ care. Further larger studies are needed to better establish the complex crosstalk between BPSD and frailty. Abbreviations ADL: Activities of Daily Living IADL: Instrumental Activities of Daily Living CIRS: Cumulative Illness Rating Scale CFS: Clinical Frailty Scale MMSE: Mini Mental State Examination NPI: Neuropsychiatric Inventory BPSD: Behavioral and Psychological Symptoms of Dementia MCI: Mild Cognitive Impairment CGA: Comprehensive Geriatric Assessment ANOVA: Analysis of variance AD: Alzheimer Disease POCD: Postoperative Cognitive Dysfunction POD: Postoperative delirium Declarations Ethics approval and consent to participate The study protocol complied with the Declaration of Helsinki and was approved by the local Ethic Committee (CEAVNO, approval number 22187). Consent for publication Not applicable. Availability of data and materials The data that support the findings of this study are available on request from the corresponding author [CO] Competing interests The authors declare that they have no competing interests Funding No funding was received to assist with the preparation of this manuscript. Authors' contributions SR and VC: study concept and design. Manuscript proof reading GC, BL, IT, EB, MGB, RP, LDC: acquisition of subjects and management of the dataset; manuscript drafting SR, VC and CO: analysis and interpretation of the data, manuscript completion AV and FM: study design, data and manuscript revision References Gao S, Burney HN, Callahan CM, Purnell CE, Hendrie HC. Incidence of Dementia and Alzheimer Disease Over Time: A Meta-Analysis. J Am Geriatr Soc. 2019;67(7):1361–9. Hugo J, Ganguli M. Dementia and cognitive impairment: epidemiology, diagnosis, and treatment. Clin Geriatr Med. 2014;30(3):421–42. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3969738","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276624851,"identity":"d66d74bd-a1ad-44d3-81fb-3ad5d79ffbb4","order_by":0,"name":"Sara Rogani","email":"","orcid":"","institution":"University of Pisa","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Rogani","suffix":""},{"id":276624852,"identity":"cf4b328b-7206-4bbd-b4d9-c786e27516de","order_by":1,"name":"Valeria Calsolaro","email":"","orcid":"","institution":"University of 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Pisa","correspondingAuthor":false,"prefix":"","firstName":"Irene","middleName":"","lastName":"Taverni","suffix":""},{"id":276624856,"identity":"4fdbdc1e-8e88-4bc8-990d-ac138e0bcb94","order_by":5,"name":"Elena Bianchi","email":"","orcid":"","institution":"University of Pisa","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"Bianchi","suffix":""},{"id":276624857,"identity":"9285e84f-b5b6-42f3-9ae0-51df1e8b1acf","order_by":6,"name":"Maria Giovanna Bianco","email":"","orcid":"","institution":"University of Pisa","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Giovanna","lastName":"Bianco","suffix":""},{"id":276624858,"identity":"86ad1ac5-e026-4664-b123-f34a5e5f75b6","order_by":7,"name":"Rosanna Pullia","email":"","orcid":"","institution":"University of Pisa","correspondingAuthor":false,"prefix":"","firstName":"Rosanna","middleName":"","lastName":"Pullia","suffix":""},{"id":276624859,"identity":"3998b539-707f-4a11-9681-fe8bd0fc1170","order_by":8,"name":"Ludovica Di Carlo","email":"","orcid":"","institution":"University of Pisa","correspondingAuthor":false,"prefix":"","firstName":"Ludovica","middleName":"Di","lastName":"Carlo","suffix":""},{"id":276624860,"identity":"496f47f2-0321-4701-a38a-d279046acd70","order_by":9,"name":"Chukwuma Okoye","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYDACCQZmKIsNRNgwAPlAlgHxWtJgWvDoQdNyGMbCrYV/do+xMW/bNnkG9rbExzwV5xO3s3OnPWAo+IPbkjtnjJN5224bNvAcO2zMc+Z24s5m3u0G+BxmIJFjfDi37TZjg0R6mzRQb+KGw7zbJIjRYg/R8u8ccVqSgVoSGyTSjknzNhwgrEXiRlqx8Z9zt5PbeI4lG845lmwM1LLdIMHAGKcW/hnJmyVnlN227WdvM3zwpsZOdsP5s9sefPgjh1MLHIDigokHxksgrAECGH8Qq3IUjIJRMApGFAAAbItQZg7oChIAAAAASUVORK5CYII=","orcid":"","institution":"University of Pisa","correspondingAuthor":true,"prefix":"","firstName":"Chukwuma","middleName":"","lastName":"Okoye","suffix":""},{"id":276624861,"identity":"41847f94-0cd2-4dbe-a72c-8b26182bebb8","order_by":10,"name":"Agostino Virdis","email":"","orcid":"","institution":"University of Pisa","correspondingAuthor":false,"prefix":"","firstName":"Agostino","middleName":"","lastName":"Virdis","suffix":""},{"id":276624862,"identity":"63fdff53-2ba2-40a0-95a6-26ab8d06f493","order_by":11,"name":"Fabio Monzani","email":"","orcid":"","institution":"University of Pisa","correspondingAuthor":false,"prefix":"","firstName":"Fabio","middleName":"","lastName":"Monzani","suffix":""}],"badges":[],"createdAt":"2024-02-19 10:34:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3969738/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3969738/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52301211,"identity":"09534ccc-e94e-4ee1-b3ce-eabe255b8943","added_by":"auto","created_at":"2024-03-08 18:37:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":387940,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNetwork analysis of correlation between CFS and neuropsychiatric symptoms\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations: \u003c/strong\u003eCFS_b: clinical frailty scale at baseline\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3969738/v1/051a0860e88b1f11c81dd86a.png"},{"id":54898400,"identity":"649448b6-5f35-463d-a49c-01cb2feebfa2","added_by":"auto","created_at":"2024-04-18 09:41:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":743391,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3969738/v1/dbc3ff62-aa3a-4973-aef6-12f36cddc7d1.pdf"},{"id":52301210,"identity":"980bed65-a4e8-4fd7-b9e5-637e886ee32a","added_by":"auto","created_at":"2024-03-08 18:37:55","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":18821,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-3969738/v1/b496726b19a2fb7b775e0dc4.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Frailty and behavioral and psychological symptoms of dementia: a single center study","fulltext":[{"header":"Background","content":"\u003cp\u003eDementia is a clinical syndrome characterized by progressive decline in multiple cognitive domains and loss of independence in activities of daily living; affecting 47\u0026nbsp;million people worldwide, dementia is a growing public health issue with considerable economic impact, with ageing as a major risk factor, as the prevalence of dementia almost doubles every five years after 65 years of age [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Alongside the cognitive symptoms, alterations in personality and behavioral changes, such as agitation, apathy, aggression, psychosis, hallucinations and delusions, may arise. Behavioral and Psychological Symptoms of Dementia (BPSD) may be among the earliest signs of cognitive decline [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. BPSD clinical presentation varies greatly among individuals, having unpredictable courses, and could fluctuate in intensity and switch to one another over time; thus, considerable distress to both patients and caregivers is often reported [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. BPSD are associated with several negative outcomes, such as faster cognitive decline and progression to more severe stages of dementia, loss of independence, increased risk for secondary complications such as falls and fractures, representing the leading reason for higher hospitalization rates and early institutionalization [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Neuropsychiatric symptoms may be present very early in the time course of cognitive impairment, some of them, like depression, may be present very early, sometimes in the MCI phase (Mild Cognitive Impairment), with a prevalence ranging from 25\u0026ndash;40% in clinical studies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. BPSD can be grouped into distinct clusters, according to similar features, and few possible classification has been hypothesized [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe existence of behavioral subsyndromes, with each group of symptoms reflecting a different prevalence, timeline, biological and psychosocial factors, can help identifying the possible correlations between BPSD and clinical variables, outlining specific interventions targeting BPSD subsyndromes rather than individual symptoms [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eConsidering that dementia mainly affect older people, it would be interesting to evaluate the possible link to other geriatric syndromes, and in particular to frailty. Frailty is defined as an aging-related syndrome, characterized by increased vulnerability to adverse events, with reduced tolerance to medical and surgical interventions [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Frail older patients often present with an increased burden of symptoms and are predisposed to negative health outcomes, such as falls, fractures, hospitalization, disability, poor quality of life, with higher risk of institutionalization.\u003c/p\u003e \u003cp\u003eCurrent evidence in the literature has shown a strong correlation between frailty and cognitive disorders, while literature about the possible correlation between BPSD and frailty is scarce. Aim of the current study was to evaluate the possible correlation between frailty and BPSD, clustered, according to Aalten et al, as \u0026ldquo;mood apathy\u0026rdquo; (depression, apathy, sleep disturbances, appetite disturbances), \u0026ldquo;psychosis\u0026rdquo; (delusions, hallucinations and anxiety) and \u0026ldquo;hyperactivity\u0026rdquo; (agitation, elation, motor aberrant behavior, irritability, disinhibition) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], in a population of older patients with dementia, at baseline and over time across a year follow-up (6 and 12 months). Moreover, the direction strength of the potential association between single BPSD and frailty was evaluated.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThis is a longitudinal, single center study. Patients referred to our Memory Clinic aged 65 years old and more, presenting with cognitive complaint were consecutively enrolled. The study protocol complied with the Declaration of Helsinki and was approved by the local Ethic Committee (CEAVNO, approval number 22187). Informed consent was acquired from patients or next of kin, as per protocol. Demographic characteristics and clinical history were obtained, along with Comprehensive Geriatric Assessment (CGA) and physical and functional examination. CGA was performed by using the following scales: Cumulative Illness Rating Scale (CIRS-c) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], Basic (ADL) and Instrumental (IADL) Activities of Daily Living [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], Mini Mental State Examination (MMSE) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Frailty was assessed using the visual analogic scale Clinical Frailty Scale (CFS) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Patients were further categorized as \u0026ldquo;severely frail\u0026rdquo;, \u0026ldquo;mild/moderately frail\u0026rdquo; and \u0026ldquo;robust\u0026rdquo; on the basis of CFS score (CFS respectively, \u0026ge; 7, 4\u0026ndash;6 and \u0026le;\u0026thinsp;3). The NPI scale was used in order to assess the presence and severity of neuropsychiatric symptoms; information for the NPI was obtained from the caregiver. According to Aalten \u003cem\u003eet al\u003c/em\u003e. BPSD were classified in three different clusters: \u0026ldquo;mood/apathy\u0026rdquo;, \u0026ldquo;psychosis\u0026rdquo; and \u0026ldquo;hyperactivity\u0026rdquo; [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Patients were assigned to a cluster according to the presence of at least one symptom reported at the NPI scale. Patients were evaluated at baseline and 6 and 12 months follow up visits; we have allowed a time window between 5 and 7 months for the first follow up, and 11\u0026ndash;13 months for the second visit.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed by using SPSS 21.0 statistical software package (SPSS Inc., Chicago, IL). Demographic and clinical characteristics among groups were compared using Analysis of variance (ANOVA) for continuous normally distributed variables and Chi-square test (χ2) for categorical or dichotomous variables. Continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, ordinal variables as median and interquartile range, and categorical variables as percentage.\u003c/p\u003e \u003cp\u003eOne-way repeated measures analysis of variance (ANOVA) with Bonferroni correction was used to compares means for continuous variables (ADL, IADL, MMSE, CFS) at 6 and 12 months follow up visits. We used linear regression to estimate the association between the number of symptoms of all the three BPSD clusters and CFS score; logistic regression was used to analyze the relationship between categorical variables, such as the presence of one or more symptoms of a particular cluster and multiple influencing factors, including ADL, IADL, CFS, MMSE, age. Stepwise regression was performed, considering age, CFS, ADL, IADL, MMSE and CIRS scores as independent variables, to evaluate the possible contribution of single factors to the correlation with BPSD Statistical significance was assigned for \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. We also developed a network analysis with the secondary endpoint of identify the most influent symptom in relation to the frailty degree of our population. The nodes represent various variables, including different type of BPSD and other factors like CFS and CIRS. The edge may be positive (e.g. positive correlation) or negative (e.g. negative correlation) and the polarity of the relationship is represented graphically using different colored lines, blue for positive relationships and red for negatives relationships. Varying the thickness and color density of the edges we underlined the strength of the relationships.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 209 patients referred to our Outpatient clinic from 2018 to 2021 with a clinical diagnosis of dementia (71.3% women; mean age = 83.24\u0026plusmn;4.98 years) were enrolled. The main demographic and clinical characteristics of the studied subjects are summarized in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1:\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003echaracteristics\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;of the study population\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"539\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.962825278810406%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.799256505576208%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e209\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e6 months follow up\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e146\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.234200743494423%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e12 months follow up\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e98\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.962825278810406%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (mean\u0026plusmn;SD)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.799256505576208%\" valign=\"top\"\u003e\n \u003cp\u003e83.24\u0026plusmn;4.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.234200743494423%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.962825278810406%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender F (%)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.799256505576208%\" valign=\"top\"\u003e\n \u003cp\u003e71.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.234200743494423%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.962825278810406%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCIRS score (mean\u0026plusmn;SD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.799256505576208%\" valign=\"top\"\u003e\n \u003cp\u003e9.26\u0026plusmn;5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.234200743494423%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.962825278810406%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCIRS-c (mean\u0026plusmn;SD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.799256505576208%\" valign=\"top\"\u003e\n \u003cp\u003e1.35\u0026plusmn;1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.234200743494423%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.962825278810406%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCIRS-s (mean\u0026plusmn;SD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.799256505576208%\" valign=\"top\"\u003e\n \u003cp\u003e1.67\u0026plusmn;0.8 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.234200743494423%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.962825278810406%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCFS (median, IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.799256505576208%\" valign=\"top\"\u003e\n \u003cp\u003e5 (1)\u003csup\u003e*,#\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003e6 (1.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.234200743494423%\" valign=\"top\"\u003e\n \u003cp\u003e6 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.962825278810406%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eADL (median, IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.799256505576208%\" valign=\"top\"\u003e\n \u003cp\u003e5 (3)\u003csup\u003e*,#,^\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003e4(3.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.234200743494423%\" valign=\"top\"\u003e\n \u003cp\u003e3(3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.962825278810406%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIADL (median, IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.799256505576208%\" valign=\"top\"\u003e\n \u003cp\u003e3(4)\u003csup\u003e*,#,^\u003c/sup\u003e \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003e2(4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.234200743494423%\" valign=\"top\"\u003e\n \u003cp\u003e1(3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.962825278810406%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMMSE (mean \u0026plusmn; SD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.799256505576208%\" valign=\"top\"\u003e\n \u003cp\u003e19.08\u0026plusmn;5.0\u003csup\u003e*,#,^\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003e17.71\u0026plusmn;5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.234200743494423%\" valign=\"top\"\u003e\n \u003cp\u003e17.02\u0026plusmn;5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.962825278810406%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNPI (frequency x severity) (mean\u0026plusmn;SD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.799256505576208%\" valign=\"top\"\u003e\n \u003cp\u003e6.63\u0026plusmn;6.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003e7.53\u0026plusmn;7.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.234200743494423%\" valign=\"top\"\u003e\n \u003cp\u003e7.85\u0026plusmn;7.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.962825278810406%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNPI distress\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(mean \u0026plusmn; SD)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.799256505576208%\" valign=\"top\"\u003e\n \u003cp\u003e3.98\u0026plusmn;3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.00371747211896%\" valign=\"top\"\u003e\n \u003cp\u003e4.83\u0026plusmn;4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.234200743494423%\" valign=\"top\"\u003e\n \u003cp\u003e4.92\u0026plusmn;4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* p\u0026lt;0.05 between b and 6 months\u003c/p\u003e\n\u003cp\u003e# p\u0026lt;0.05 between b and 12 months\u003c/p\u003e\n\u003cp\u003e^ p\u0026lt;0.05 between 6m and 12 months\u003c/p\u003e\n\u003cp\u003eAbbreviations.\u0026nbsp;CIRS: Cumulative Illness Rating Scale; CFS: clinical frailty scale; ADL: activities of daily living; IADL: instrumental activities of daily living; MMSE: mini mental state examination; NPI: neuropsychiatric inventory; IQR: interquartile range.\u003c/p\u003e\n\u003cp\u003eAt baseline, the study cohort showed a low burden of comorbidity (mean CIRS-C score 1.35\u0026plusmn;1.5), a mild degree of frailty with a need for help in high order IADLs [CFS 5 (IQR 1), ADL 5 (IQR 3), IADL 3 (IQR 4)], and moderate cognitive decline (MMSE score 19.08\u0026plusmn;5.0).NPI scale for the assessment of BPSD showed a moderate degree of severity of symptoms and caregiver distress (NPI axb 6.63\u0026plusmn;6.6, NPI distress 3.98\u0026plusmn;3.6). The repeated measure ANOVA conducted over the three timepoints showed that each pairwise difference was significant.\u0026nbsp;The results of the ANOVA indicated a significant time effect on functional status, with worsening of ADL and IADL over time [ADL Wilks\u0026rsquo; Lambda=0.744, F(2.80)=13.75, p\u0026lt;0.001, \u0026eta;\u003csup\u003e2\u003c/sup\u003e=0.256, IADL Wilks\u0026rsquo; Lambda=0.71, F(2.80)=16.3, p\u0026lt;0.001, \u0026eta;\u003csup\u003e2\u003c/sup\u003e=0.29, respectively]. Likewise, there was a significant progression of cognitive impairment as measured with MMSE and a significant worsening of frailty by CFS [MMSE Wilks\u0026rsquo; Lambda=0.751, F(2,73)=12.11, p\u0026lt;0.001, \u0026eta;\u003csup\u003e2\u003c/sup\u003e=0.249, CFS Wilks\u0026rsquo; Lambda=0.749, F(2.79)=13.224, p\u0026lt;0.001, \u0026eta;\u003csup\u003e2\u003c/sup\u003e=0.241]. \u0026nbsp;In particular, ADL significantly worsened between baseline and 6 months follow up (median values 5\u0026plusmn;3 and 4\u0026plusmn;3.2 respectively, p=0.005), between 6 months and 12 months (median values 4\u0026plusmn;3 and 3, respectively p\u0026lt;0.001) and between baseline and 12 months (p\u0026lt;0.001). IADL worsening was significant between baseline and 6 months follow-up (median values 3\u0026plusmn;4 and 2\u0026plusmn;4 respectively, p=0.002), between 6 and 12 months (median values 2\u0026plusmn;4 and 1\u0026plusmn;3 respectively, p\u0026lt;0.001) and baseline and 12 months (p\u0026lt;0.001). The same trend was observed for the MMSE score, with a progressive significant worsening baseline and 6 months (mean values 19.08\u0026plusmn;5 and 17.71\u0026plusmn;5.8 respectively, p=0.041), between 6 and 12 months (mean values 17.71\u0026plusmn;5.8 and 17.07\u0026plusmn;5.8 respectively, p\u0026lt;0.01) and between baseline and 12 months as well. The worsening of CFS was significant between baseline and 6 and 12 months follow up (median value 5\u0026plusmn;1 and 6\u0026plusmn;1.25 respectively, p\u0026lt;0.001), and between 6 and 12 months (median value 6\u0026plusmn;1.25 and 6\u0026plusmn;1.5, respectively, p=0.025).\u0026nbsp;The most represented group was the mild/moderately frail one (n=155); lower numbers were seen in the robust (n=18) and severely frail (n=36) ones. Within the mild/moderately frail subgroup, about 55.5% of the patients showed at least one symptom of the \u0026quot;mood/apathy\u0026quot; cluster at baseline and this percentage remained consistent throughout the follow-up period. Among the severely frail subgroup, this percentage was significantly higher, with 69.4% (p=0.04) exhibiting at least one symptom of this cluster at baseline. Similarly, the percentage of patients with symptoms in the \u0026quot;psychosis\u0026quot; and \u0026quot;hyperactivity\u0026quot; clusters remained high among the severely frail patients as opposed to the mild-moderately frail group. The results are shown in Appendix. At linear regression, the number of symptoms of the hyperactivity cluster correlated with the degree of frailty, at baseline and at 6 months and 12 months follow up (p\u0026lt;0.001, p=0.022, p=0.028 respectively).\u0026nbsp;\u0026nbsp;Conversely, no association was observed with both the mood/apathy and the psycosis clusters.\u0026nbsp;To evaluate the possible contribution of single factors to the correlation with BPSD clusters, a stepwise regression was performed, considering age, CFS, ADL, IADL, MMSE and CIRS scores as independent variables. At baseline the loss of independence in IADL resulted the independent risk factor for the \u0026ldquo;hyperactivity\u0026rdquo; cluster (p\u0026lt;0.001) and, the burden of comorbidity evaluated by CIRS-C score for the \u0026ldquo;psychosis\u0026rdquo; cluster, (p=0.016). While the burden of comorbidity (CIRS-C), the degree of frailty (CFS) and the age concurred as significant risk factors for symptoms of the \u0026ldquo;mood/apathy\u0026rdquo; cluster, although with different strength (p=0.008, p= 0.004 and p\u0026lt;0.001 respectively) (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Stepwise Regression for the hyperactivity cluster\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.80243161094225%\" colspan=\"2\" rowspan=\"2\" valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"26.595744680851062%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnstandardized Coefficients\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.84498480243161%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStandardized Coefficients\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eBeta\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" rowspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003et\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.118541033434651%\" rowspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eSign.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"54.285714285714285%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.714285714285715%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eStandard error\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.103343465045593%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.699088145896656%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e(Costant)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.1914893617021276%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.246200607902736%\" valign=\"top\"\u003e\n \u003cp\u003e.571\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.158054711246201%\" valign=\"top\"\u003e\n \u003cp\u003e.050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.84498480243161%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" valign=\"top\"\u003e\n \u003cp\u003e11.492\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.118541033434651%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"4.103343465045593%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"30.699088145896656%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIADL_b\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.1914893617021276%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.246200607902736%\" valign=\"top\"\u003e\n \u003cp\u003e-.058\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.158054711246201%\" valign=\"top\"\u003e\n \u003cp\u003e.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.84498480243161%\" valign=\"top\"\u003e\n \u003cp\u003e-.305\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.638297872340425%\" valign=\"top\"\u003e\n \u003cp\u003e-4.612\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.118541033434651%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eDependent variable: HYPERACTIVITY\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviation:\u0026nbsp;\u003c/strong\u003eIADL_b: instrumental activities of daily living_baseline\u003c/p\u003e\n\u003cp\u003eIn order to better understand the complex pattern of relationships between the different factors, we performed a network analysis. In our model represented in Figure 1not all nodes are equally important in determining the network\u0026rsquo;s structure; clustering of nodes that are highly interconnected among themselves and poorly connected with nodes outside the cluster can be identified. The degree of frailty, expressed by CFS, relates to behavioral and psychological symptoms of the hyperactivity cluster, such as agitation and motor aberrant activity; the relationship is still positive although not so strong with other symptoms like apathy and hallucinations. The clustering of nodes also reflects the clustering of different BPSD in the three subgroups we identified: psychosis, mood/apathy and hyperactivity clusters. Logistic regression showed that at baseline, the reduced ability to perform instrumental activities of daily living (IADL) was associated with symptoms of the \u0026ldquo;hyperactivity\u0026rdquo; cluster (p=0.022); this finding was confirmed at 6 months follow up (p=0.003), while at 12 months a strong association emerged with CFS (p=0.008). A significant association between the presence of one of more symptoms of the \u0026ldquo;mood/apathy\u0026rdquo; cluster with both the degree of frailty (CFS) and the age (p=0.019, p=0.032, respectively) was obtained at baseline.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe aim of our study was to evaluate the impact of frailty, on the presence, onset and progression of specific clusters of BPSD in older patients referred to our Memory Clinic, at baseline and during follow up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCurrent evidence in the literature has shown a strong correlation between frailty and cognitive disorders, including mild cognitive impairment and dementia, suggesting that cognition and frailty may interact within a cycle of age-related decline\u0026nbsp;[16-18]. The degree of frailty could contribute to cognitive decline, with frail older adults at higher risk of developing dementia compared to robust ones\u0026nbsp;[19-22].\u003c/p\u003e\n\u003cp\u003eDespite the ample literature existing on the association between frailty and dementia, to the best of our knowledge, scanty data are available on the correlation between the degree of frailty and BPSD clusters. Sugimoto \u003cem\u003eet al.\u003c/em\u003e evaluated the association between physical frailty and BPSD in a cohort of patients with AD (Alzheimer Disease), with physical frailty calculated with 38 items Frailty Index (FI). The results of the study showed that presence of physical frailty and pre-frailty increased the BPSD burden in patients with AD\u0026nbsp;[23]. That is confirmed in our cohort, where the cluster of subjects with higher comorbidity burden and lower cognitive and physical performance showed higher prevalence of psychiatric symptoms.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong our cohort of older patients, the prevalence of neuropsychiatric symptoms was different among the \u0026ldquo;robust\u0026rdquo;, \u0026ldquo;mild/moderate frail\u0026rdquo; and \u0026ldquo;severely frail\u0026rdquo; subgroups. Even though the most represented group was the \u0026ldquo;mild/moderately frail\u0026rdquo; one, the percentage of patients presenting with at least one symptom per cluster was higher in the \u0026ldquo;severely frail\u0026rdquo; compared to the other groups. In particular, almost two third of patients of the \u0026ldquo;severely frail\u0026rdquo; subgroup showed neuropsychiatric symptoms of the \u0026ldquo;mood/apathy\u0026rdquo; cluster at baseline, remaining substantially stable during follow-up. Similarly to what observed for the \u0026ldquo;mood/apathy\u0026rdquo; cluster, the prevalence of \u0026ldquo;severely frail\u0026rdquo; patients with neuropsychiatric symptoms of the \u0026ldquo;psychosis\u0026rdquo; and \u0026ldquo;hyperactivity\u0026rdquo; clusters was always higher compared to patients of the \u0026ldquo;mild/moderate frail\u0026rdquo; subgroup, suggesting that the degree of frailty could be associated to the burden of BPSD symptoms. Accordingly, as shown in the network analysis graph, the degree of frailty at baseline is positively correlated to agitation and motor aberrant activity, both belonging to the hyperactivity cluster. However, the contributing role of BPSD to frailty and, possibly, the reverse is yet to be determined. Consistently, regression analysis confirmed that reduced score in the IADL appears to be correlated with symptoms of the hyperactivity cluster, which may suggest either that the loss in higher functions could be a trigger for aberrant behaviors in subjects with cognitive impairment, or that the presence of hyperactivity symptoms may affect the ability of efficiently perform complex activities of daily living. It also should be acknowledged that this study has been conducted in a time window comprehensive of the pandemic crisis, when social interactions were forbidden, or at least limited. Thus, physical or behavioral worsening might partially be a consequence of the social situation, and studies on a larger scale would be desirable. \u0026nbsp;Although literature about the possible correlation between BPSD and frailty is scarce, a lot has been written about the association between frailty and delirium. Postoperative Cognitive Dysfunction (POCD) and delirium (POD) are the most common perioperative cognitive complications in older patients undergoing different surgical procedures, such as spine surgery\u0026nbsp;[24]\u0026nbsp;or major noncardiac surgery\u0026nbsp;[25]. A meta-analysis by Zhang \u003cem\u003eet al.\u0026nbsp;\u003c/em\u003eof a total of 30 independent studies from 9 countries, consisting of 217623 hospitalized patients (medical, surgical, emergency and critical illness patients), showed an increased risk of delirium in frail patients compared to those not frail\u0026nbsp;[26].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong the different BPSD clusters,\u0026nbsp;hyperactivity shares some features with delirium, in particular with hyperkinetic and mixed delirium. Considering that delirium usually presents with symptoms that are common to the \u0026quot;hyperactivity\u0026quot; cluster, the association between this cluster and frailty do not surprise. Moreover, it should be considered the possibility that some diagnosis of delirium, especially if and when lasting for long time after discharge, could rather be a symptom of BPSD and a sign of dementia, supporting the need of cognitive follow up of all patients developing in-hospital delirium. The results of our research also suggest the usefulness of an in-depth study in a larger cohort of patients with cognitive impairment and BPSD. A strength of our study is that the cohort of patients could be considered representative of the general oldest population, since our sample is composed by patients referred from the community for cognitive complaint.\u003c/p\u003e\n\u003cp\u003eEven though the results of the study are promising and interesting, we have to acknowledge few limitations. First of all, the patients enrolled have a clinical diagnosis of Alzheimer\u0026rsquo;s Disease or mixed dementia, based on clinical criteria and structural imaging, but without the biomarkers, therefore we could not exclude some misdiagnosis. However, patients with highly suspicious frontotemporal dementia, Lewy body dementia, Parkinson\u0026rsquo;s disease dementia or post-stroke dementia were not included in the dataset. Moreover, the patients presenting BPSD were a small number, and a wider cohort would have been more informative, especially enrolling more patients \u0026ldquo;robust\u0026rdquo; and \u0026ldquo;severely frail\u0026rdquo;. We also acknowledge that 1-year follow up might not be sufficient to draw conclusions about the progression of two chronic and progressive diseases like dementia and frailty. However, being literature about this topic still scarce, we considered an initial short-term evaluation a possible starting point for further and more powered studies. A further analysis evaluating not just the single cluster, but also the combination of them would certainly be more informative and representative of the general population, but the present cohort is not sufficiently large for further division in subgroups.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe purpose of the current study was to determine if the presence of physical frailty, as determined by the CFS, could represent a risk factor for the development and progression of BPSD in older patients with AD. One of the most significant findings \u0026nbsp;emerged from this study is the association between frailty and the number of neuropsychiatric symptoms of the \u0026ldquo;hyperactivity\u0026rdquo; cluster; however, whether the loss of independence is a possible cause of frailty or \u003cem\u003eviceversa\u003c/em\u003e is still to be determined.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe results of this study suggest that the assessment of frailty may help identifying patients at risk of developing behavioral and psychological symptoms of dementia, and could provide the clinicians with a time-window to target intervention in the earliest phases of both frail condition and BPSD. This is of crucial importance, especially because an early intervention may benefit from non-pharmacological approaches, saving patients from prescription of antipsychotics drugs which are linked to several adverse events. Given the importance of frailty assessment, especially in the oldest population, a standardized approach to physical frailty evaluation in future clinical studies is highly desirable and would provide clinicians with simple and highly efficient tools for the patients\u0026rsquo; care. Further larger studies are needed to better establish the complex crosstalk between BPSD and frailty.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADL: Activities of Daily Living\u003c/p\u003e\n\u003cp\u003eIADL: Instrumental Activities of Daily Living\u003c/p\u003e\n\u003cp\u003eCIRS: Cumulative Illness Rating Scale\u003c/p\u003e\n\u003cp\u003eCFS: Clinical Frailty Scale\u003c/p\u003e\n\u003cp\u003eMMSE: Mini Mental State Examination\u003c/p\u003e\n\u003cp\u003eNPI: Neuropsychiatric Inventory\u003c/p\u003e\n\u003cp\u003eBPSD:\u0026nbsp;Behavioral and Psychological Symptoms of Dementia\u003c/p\u003e\n\u003cp\u003eMCI: Mild Cognitive Impairment\u003c/p\u003e\n\u003cp\u003eCGA: Comprehensive Geriatric Assessment\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eANOVA: Analysis of variance\u003c/p\u003e\n\u003cp\u003eAD: Alzheimer Disease\u003c/p\u003e\n\u003cp\u003ePOCD: Postoperative Cognitive Dysfunction\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePOD: Postoperative delirium\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch4\u003eEthics approval and consent to participate\u003c/h4\u003e\n\u003cp\u003eThe study protocol complied with the Declaration of Helsinki and was approved by the local Ethic Committee (CEAVNO, approval number 22187).\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003eConsent for publication\u003c/h4\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch4\u003eAvailability of data and materials\u003c/h4\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author [CO]\u003c/p\u003e\n\u003ch4\u003eCompeting interests\u003c/h4\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003ch4\u003eFunding\u003c/h4\u003e\n\u003cp\u003eNo funding was received to assist with the preparation of this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003eAuthors\u0026apos; contributions\u003c/h4\u003e\n\u003cp\u003eSR and VC: study concept and design. Manuscript proof reading\u003c/p\u003e\n\u003cp\u003eGC, BL, IT, EB, MGB, RP, LDC: acquisition of subjects and management of the dataset; manuscript drafting\u003c/p\u003e\n\u003cp\u003eSR, VC and CO: analysis and interpretation of the data, manuscript completion\u003c/p\u003e\n\u003cp\u003eAV and FM: study design, data and manuscript revision\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGao S, Burney HN, Callahan CM, Purnell CE, Hendrie HC. Incidence of Dementia and Alzheimer Disease Over Time: A Meta-Analysis. J Am Geriatr Soc. 2019;67(7):1361\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHugo J, Ganguli M. Dementia and cognitive impairment: epidemiology, diagnosis, and treatment. Clin Geriatr Med. 2014;30(3):421\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCalsolaro V, Femminella GD, Rogani S, Esposito S, Franchi R, Okoye C, Rengo G, Monzani F. Behavioral and Psychological Symptoms in Dementia (BPSD) and the Use of Antipsychotics. Pharmaceuticals (Basel) 2021, 14(3).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao QF, Tan L, Wang HF, Jiang T, Tan MS, Tan L, Xu W, Li JQ, Wang J, Lai TJ, et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord. 2016;190:264\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeardorff WJ, Grossberg GT. Behavioral and psychological symptoms in Alzheimer's dementia and vascular dementia. Handb Clin Neurol. 2019;165:5\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTible OP, Riese F, Savaskan E, von Gunten A. Best practice in the management of behavioural and psychological symptoms of dementia. Ther Adv Neurol Disord. 2017;10(8):297\u0026ndash;309.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIsmail Z, Elbayoumi H, Fischer CE, Hogan DB, Millikin CP, Schweizer T, Mortby ME, Smith EE, Patten SB, Fiest KM. Prevalence of Depression in Patients With Mild Cognitive Impairment: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2017;74(1):58\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAalten P, de Vugt ME, Lousberg R, Korten E, Jaspers N, Senden B, Jolles J, Verhey FR. Behavioral problems in dementia: a factor analysis of the neuropsychiatric inventory. Dement Geriatr Cogn Disord. 2003;15(2):99\u0026ndash;105.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAalten P, Verhey FR, Boziki M, Bullock R, Byrne EJ, Camus V, Caputo M, Collins D, De Deyn PP, Elina K, et al. Neuropsychiatric syndromes in dementia. Results from the European Alzheimer Disease Consortium: part I. Dement Geriatr Cogn Disord. 2007;24(6):457\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLyketsos CG, Breitner JC, Rabins PV. An evidence-based proposal for the classification of neuropsychiatric disturbance in Alzheimer's disease. Int J Geriatr Psychiatry. 2001;16(11):1037\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoogendijk EO, Afilalo J, Ensrud KE, Kowal P, Onder G, Fried LP. Frailty: implications for clinical practice and public health. Lancet. 2019;394(10206):1365\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParmelee PA, Thuras PD, Katz IR, Lawton MP. Validation of the Cumulative Illness Rating Scale in a geriatric residential population. J Am Geriatr Soc. 1995;43(2):130\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKatz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of Illness in the Aged. The Index of Adl: A Standardized Measure of Biological and Psychosocial Function. JAMA. 1963;185:914\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonroe T, Carter M. Using the Folstein Mini Mental State Exam (MMSE) to explore methodological issues in cognitive aging research. Eur J Ageing. 2012;9(3):265\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChurch S, Rogers E, Rockwood K, Theou O. A scoping review of the Clinical Frailty Scale. BMC Geriatr. 2020;20(1):393.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorges MK, Canevelli M, Cesari M, Aprahamian I. Frailty as a Predictor of Cognitive Disorders: A Systematic Review and Meta-Analysis. Front Med (Lausanne). 2019;6:26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi CL, Chang HY, Shyu YL, Stanaway FF. Relative Role of Physical Frailty and Poor Cognitive Performance in Progression to Dementia. J Am Med Dir Assoc. 2021;22(7):1558\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobertson DA, Savva GM, Kenny RA. Frailty and cognitive impairment\u0026ndash;a review of the evidence and causal mechanisms. Ageing Res Rev. 2013;12(4):840\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlencar MA, Dias JM, Figueiredo LC, Dias RC. Frailty and cognitive impairment among community-dwelling elderly. Arq Neuropsiquiatr. 2013;71(6):362\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePanza F, Lozupone M, Solfrizzi V, Sardone R, Dibello V, Di Lena L, D'Urso F, Stallone R, Petruzzi M, Giannelli G, et al. Different Cognitive Frailty Models and Health- and Cognitive-related Outcomes in Older Age: From Epidemiology to Prevention. J Alzheimers Dis. 2018;62(3):993\u0026ndash;1012.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSearle SD, Rockwood K. Frailty and the risk of cognitive impairment. Alzheimers Res Ther. 2015;7(1):54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWallace LMK, Theou O, Darvesh S, Bennett DA, Buchman AS, Andrew MK, Kirkland SA, Fisk JD, Rockwood K. Neuropathologic burden and the degree of frailty in relation to global cognition and dementia. Neurology. 2020;95(24):e3269\u0026ndash;79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSugimoto T, Ono R, Kimura A, Saji N, Niida S, Toba K, Sakurai T. Physical Frailty Correlates With Behavioral and Psychological Symptoms of Dementia and Caregiver Burden in Alzheimer's Disease. J Clin Psychiatry 2018, 79(6).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSusano MJ, Grasfield RH, Friese M, Rosner B, Crosby G, Bader AM, Kang JD, Smith TR, Lu Y, Groff MW, et al. Brief Preoperative Screening for Frailty and Cognitive Impairment Predicts Delirium after Spine Surgery. Anesthesiology. 2020;133(6):1184\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahanna-Gabrielli E, Zhang K, Sieber FE, Lin HM, Liu X, Sewell M, Deiner SG, Boockvar KS. Frailty Is Associated With Postoperative Delirium But Not With Postoperative Cognitive Decline in Older Noncardiac Surgery Patients. Anesth Analg. 2020;130(6):1516\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang XM, Jiao J, Xie XH, Wu XJ. The Association Between Frailty and Delirium Among Hospitalized Patients: An Updated Meta-Analysis. J Am Med Dir Assoc. 2021;22(3):527\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"frailty, dementia, behavioural and psychological symptoms in dementia (BPSD), hyperactivity","lastPublishedDoi":"10.21203/rs.3.rs-3969738/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3969738/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eDementia is a devastating neurodegenerative disease widely spread, representing a huge health, social and economic burden. During the dementia time-course, Behavioral and Psychological Symptoms of Dementia (BPSD) may arise, greatly impacting on the management and outcomes of the disease. Considering that dementia mainly affects the older population, the possible link to frailty should be considered.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAim of this single centre, longitudinal study was to evaluate the correlation between frailty and BPSD in a population of older patients with dementia. BPSD were classified in three clusters: \u0026ldquo;mood/apathy\u0026rdquo; (depression, apathy, sleep disturbances, appetite disturbances), \u0026ldquo;psychosis\u0026rdquo; (delusions, hallucinations and anxiety) and \u0026ldquo;hyperactivity\u0026rdquo; (agitation, elation, motor aberrant behavior, irritability, disinhibition). Using the Clinical Frailty Scale (CFS), patients were categorized as \u0026ldquo;severely frail\u0026rdquo;, \u0026ldquo;mild/moderately frail\u0026rdquo; and \u0026ldquo;robust\u0026rdquo; (CFS\u0026thinsp;\u0026ge;\u0026thinsp;7, 4\u0026ndash;6 and \u0026le;\u0026thinsp;3, respectively).\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTwo-hundreds and nine patients (mean age 83.24\u0026thinsp;\u0026plusmn;\u0026thinsp;4.98 years) with a clinical diagnosis of dementia were enrolled. Among the \u0026ldquo;severely frail\u0026rdquo; the percentage of BPSD was higher compared to the other two groups in the three clusters. A positive correlation between frailty and \u0026ldquo;hyperactivity\u0026rdquo; cluster, at baseline and follow up visits (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, p\u0026thinsp;=\u0026thinsp;0.022, p\u0026thinsp;=\u0026thinsp;0.028 respectively) was found. This result was confirmed with the network analysis, showing that frailty, expressed by CFS, relates to agitation and motor aberrant activity.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFrailty may help identifying patients at the highest risk for developing BPDS thus, targeting intervention in the earliest phases of the disease. In-depth studies in larger cohorts of patients are needed to confirm and extend these results.\u003c/p\u003e","manuscriptTitle":"Frailty and behavioral and psychological symptoms of dementia: a single center study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-08 18:37:50","doi":"10.21203/rs.3.rs-3969738/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"096fad54-5e98-4f41-b55e-b4e7702b233a","owner":[],"postedDate":"March 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-09T06:17:24+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-08 18:37:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3969738","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3969738","identity":"rs-3969738","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}