ORIGINAL RESEARCH published: 24 July 2019 doi: 10.3389/fnagi.2019.00176 Neuropsychiatric Symptoms as Predictors of Clinical Course in Neurodegeneration. A Longitudinal Study José Manuel Santacruz Escudero 1,2,3 *, Jonathan Beltrán 1 , Álvaro Palacios 1 , Claudia Marcela Chimbí 2 , Diana Matallana 1 , Pablo Reyes 1,2 , Victor Perez-Sola 3 and Hernando Santamaría-García 1,2 * 1 Departments of Psychiatry, Physiology and Institute for Studies on the Aging, Pontificia Universidad Javeriana, Bogotá, Colombia, 2 Intellectus Memory and Cognition Center, Hospital Universitario San Ignacio, Bogotá, Colombia, 3 Department of Psychiatry and Forensic Medicine, Univesitat Autonòma de Bercelona, Barcelona, Spain Background: To study the extent to which neuropsychiatric symptoms (NPS) influence the cognitive and functional decline in frontotemporal degeneration (FTD) and Alzheimer’s disease (AD). Methods: We assessed the progression of NPS and their influence on cognitive Edited by: and functional progression in a group of FTD (n = 36) and AD patients (n = 47) Roberto Monastero, at two different stages of the disease (2.5 years). A standardized scale was used University of Palermo, Italy to assess NPS—the Columbia University Scale for Psychopathology in Alzheimer’s Reviewed by: Disease (CUSPAD)—which tracks different symptoms including depression, psychotic Katie Palmer, Catholic University of the Sacred symptoms, as well as sleep and conduct problems. In addition, in a subsample of Heart, Rome, Italy patients (AD n = 14 and FTD n = 14), we analyzed another group of NPS by using the Guanghui Wang, Neuropsychiatric Inventory (NPI). Cognitive declines were tracked by using the Montreal Soochow University, China Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE), while *Correspondence: José Manuel Santacruz Escudero functionality was tracked by using the Lawton scale and the Barthel Index. j.santacruz@javeriana.edu.co Results: The presence of NPS impacts cognitive and functional decline in both groups of Hernando Santamaría-García hernando.santamaria@javeriana.edu.co patients 2.5 years after disease onset. However, we observed a dissociable profile of the affectation of NPS in each group. In the AD group, results indicate that the progression Received: 27 October 2018 of depressive symptoms and sleep problems predict cognitive and functional decline. Accepted: 01 July 2019 Published: 24 July 2019 In contrast, the progression of a mixed group of NPS, including conduct problems and Citation: delusions, predicts cognitive and functional decline in FTD. Santacruz Escudero JM, Beltrán J, Conclusion: The presence of NPS has a critical impact on the prediction of cognitive Palacios Á, Chimbi CM, Matallana D, Reyes P, Perez-Sola V and decline in FTD and AD patients after 2.5 years of disease progression. Our results Santamaría-García H demonstrate the importance of assessing different types of NPS in neurodegenerative (2019) Neuropsychiatric Symptoms as Predictors of Clinical Course in disorders which, in turn, predict disease progression. Future studies should assess the Neurodegeneration. A role of NPS in predicting different neurocognitive pathways and in neurodegeneration. Longitudinal Study. Front. Aging Neurosci. 11:176. Keywords: frontotemporal dementia, Alzheimer’s disease, behavioral disturbances, depression, cohort studies, doi: 10.3389/fnagi.2019.00176 assessment of cognitive disorders/dementia Frontiers in Aging Neuroscience | www.frontiersin.org 1 July 2019 | Volume 11 | Article 176 Santacruz Escudero et al. Neuropsychiatric Symptoms as Predictors in Neurodegeneration INTRODUCTION Particularly, we study aimed to determine to what extent the presence of different types of NPS (including behavioral, Frontotemporal degeneration (FTD) and Alzheimer’s disease affective and psychotic symptoms among others) at early stages (AD) are prevalent neurodegenerative diseases which generate of disease progression, predict the cognitive and functional alterations in different cognitive and behavioral processes and disease progression in AD (n = 47) and FTD (n = 36) patients. have a considerable impact on the functionality of patients Considering previous studies, we expected that depression, (Piguet et al., 2011; Livingston et al., 2017). rather than other behavioral symptoms, has a predictive role of It is usual for patients with FTD to present alterations in cognitive and functional progression in AD, but not in FTD. the frontal, insular, and temporal brain areas, which are related Conversely, we expected that the conduct problems, rather than to alterations in social behavior and executive functions (Piguet depression, would be predictive of cognitive and functional et al., 2011; Rascovsky et al., 2011; Sedeño et al., 2016). In turn, deterioration in FTD. cognitive, language, and praxis alterations in AD have been associated with progressive atrophy in parieto-temporal areas MATERIALS AND METHODS (Dubois et al., 2014). Both AD and FTD tend to exhibit neuropsychiatric symptoms Participants (NPS; Ismail et al., 2016), which are considered relevant indexes Patients recruited to this study were divided into two groups. for the determination of disease severity and progression (Teng The first group included 36 patients who fulfilled the revised et al., 2007; Peters et al., 2015). Depression and apathy have criteria for probable FTD (Rascovsky et al., 2011) and presented been associated with cognitive decline and mortality in AD with prominent changes in personality and social behavior as (Teng et al., 2007; Karttunen et al., 2011; Ismail et al., 2016; verified by caregivers. They were recruited from the Bogotá Kaup et al., 2016), whereas in FTD, apathy, disinhibition and FTD Cohort (BOGFTD), largely reported in previous studies empathy impairments are the most prevalent NPS (Rascovsky (Baez et al., 2014a,b; Santamaría-García et al., 2016, 2017). et al., 2011; Brodaty et al., 2015) that impact disease progression The second group included 47 patients diagnosed with AD (Brodaty et al., 2015; Ranasinghe et al., 2016). Previous studies who were included in this study after meeting criteria outlined have shown different neurocognitive progression according in McKhann et al. (2011). Patients were recruited from the to the major type of symptom in FTD (Santamaría-García Memory Clinic of the Intellectus Memory and Cognition et al., 2016). A broad range of NPS in both AD and FTD Center, at the Hospital San Ignacio in Bogotá (Colombia). has been described including delusions and sensory-perceptual Patients underwent a standard examination battery, including alterations (hallucinations and illusions; Rubin et al., 1988; Van neurological, neuropsychiatric, and neuropsychological Dam et al., 2016; Gossink et al., 2017), as well as conduct assessments by geriatricians, psychiatrists, neurologists, and problems (Santamaría-García et al., 2016; Van Dam et al., neuropsychologists. All patients were in the early/mild stages 2016), depressive and anxiety symptoms (Brodaty et al., 2015; of the disease and did not meet the criteria for specific Sellami et al., 2018), sleep problems (Mander et al., 2016; psychiatric disorders. Patients presenting primarily with Merrilees et al., 2014) and eating changes (Ahmed et al., language deficits or a history of drug abuse, or a family history of 2015; Ringman et al., 2015). Regarding the psychotic symptoms neurodegenerative or psychiatric disorders were excluded from (including delusions and sensory-perceptive alterations such as the study. hallucinations and illusions), previous studies have reported that those symptoms can appear in both AD and FTD. Previous Initial Clinical Considerations in AD and studies have estimated the prevalence of psychotic symptoms FTD Patients in AD reached 20% and around 10% in FTD, mainly presented AD Patients in patients with C9ORF72 mutations (Mendez et al., 2008). Most of the AD patients debuted with symptoms at 68.6 years and Psychotic symptoms presented in AD and FTD are associated diagnosis was made on average 1.2 years after onset of symptoms with difficulties in episodic and working memory, poor reading (SD 0.4 years). Most of the participants debuted with cognitive of internal feelings, emotional dysregulation and inaccurate symptoms consisting of episodic memory alterations (79.5%), conclusions on reality associated with right frontal hypofunction language difficulties (43.1%) and disorientation (18.2%). A group and impaired activity of medial temporal areas (Mendez et al., of patients also coursed with depression (38.8%), anxiety (11, 2008). Although the presence of psychotic symptoms has been 1%), irritability (19.2%) and insomnia (12.1%). associated with diagnosis difficulties in FTD (Velakoulis et al., Additionally, a group of AD patients received medications 2009) and rapid cognitive decline in AD (Tchalla et al., 2018), before diagnosis, including selective serotonin reuptake to date, it is unknown to what extent the presence of those inhibitors (SSRIs; 12.6%), antipsychotic agents (19.4%), symptoms can impact cognitive and functionality decline in cholinergic agents (rivastigmine, donepezil and galantamine; both AD and FTD. 13.4%), benzodiazepines (1.5%) and GABA-A agonists Although previous studies have assessed the presence of (zopiclone and eszopiclone; 1.3%). different NPS in neurodegenerative disorders, to our knowledge, this is the first study assessing to what extent their presence FTD Patients at early stages of disease impacts the course of disease in Most of the AD patients debuted with symptoms at 60.7 years AD and FTD. and were diagnosed 1.1 years after debut symptoms on Frontiers in Aging Neuroscience | www.frontiersin.org 2 July 2019 | Volume 11 | Article 176 Santacruz Escudero et al. Neuropsychiatric Symptoms as Predictors in Neurodegeneration average (SD 0.6 years). Most of the participants debuted with Assessment of Instrumental Functionality behavioral symptoms featured by apathy (25.9%), disinhibition The Lawton scale is an instrument for assessing the instrumental (34.5%), delusions (1.9%), depression (18.5%) and anxiety activities of daily living (Lawton and Brody, 1969). This (11.1%). Furthermore, 18.1% of patients coursed with attention instrument has been used to assess the clinical progression of impairments, 15.6% with language difficulties and 27. 8% with dementia with respect to functional commitment. It contains working memory impairments. A group of FTD patients received eight items that assess functionality, including the ability to use pharmacological treatments before diagnosis was made, from the phone, go shopping, prepare food, perform household care them 17.9% received selective serotonin reuptake inhibitors and laundry, use of public transportation, as well as medication (SSRIs), 14.1% antipsychotic agents, 0.8% benzodiazepines, 0.9% and money management, with an internal consistency measured valproate and 0.6% carbamazepine. by a Cronbach’s alpha coefficient of 0.94 (Lawton and Brody, 1969; Vergara et al., 2012). The Lawton scale is an Assessment Milestones instrument previously reported for assessing functionality in Patient groups (FTD and AD) were assessed at two stages of neurodegenerative disorders (Cornelis et al., 2017). the disease progression. Patients were assessed by the same group of specialists at both stages. All enrolled patients had the Assessment of Physical Functionality same diagnosis in the first and second stages of assessment. In In addition, we used the Barthel index (Mahoney and the first stage, patients were assessed at the time of diagnosis. Barthel, 1965), which was introduced as a way to measure The second assessment took place 2.5 years after the first the impairments of patients in their neuromuscular and (FTD mean = 2.4 years, SD = 1.2 vs. AD mean = 2.6 years, musculoskeletal function, placing a strong focus on the spared SD = 1.1). In each stage, patients in both groups were assessed activity of inferior extremities. The index is an ordinal scale with neurocognitive measures, as well as with measures of NPS comprising 10 activities of daily living, including sphincter (see below). As reported in previous studies (Baez et al., 2014b; control. The original Barthel index was scored in steps of five Sedeño et al., 2017), we observed differences in the age at disease points to give a maximum total score of 100. The Lawton scale is onset (see Table 1). an instrument previously reported for assessing functionality in neurodegenerative disorders including FTD and AD (Merrilees et al., 2013; Liljegren et al., 2015). Cognitive Assessment Global cognitive performance was assessed in two stages through Assessment of Neuropsychiatric Symptoms (NPS) a comprehensive set of measures, using the Montreal Cognitive The assessment of NPS, including delusions, sensory-perceptive Assessment (MoCA; Nasreddine et al., 2005; Freitas et al., 2012; alterations (hallucinations and illusions), conduct problems, Delgado et al., 2017) and the Mini-Mental State Examination sleep problems, depression, anxiety, and changes in eating (MMSE; Folstein et al., 1983). The MoCA scale has a sensitivity patterns, was conducted at two stages using the Columbia above 87% and a specificity of 90% with a cut-off point of 26, and University Scale for Psychopathology in Alzheimer’s Disease a sensitivity of 87% and a specificity of 87% with a cut-off lower (CUSPAD; Devanand et al., 1992; Suárez-González et al., 2013). than 18 points. It is composed of 19 items that evaluate eight CUSPAD is a quick and easy to use standardized instrument cognitive domains, including executive skills, denomination, that provides information regarding neurodegenerative memory, attention, language, abstraction, deferred memory and psychopathology. Classical reports calculated that this orientation (Nasreddine et al., 2005; Pedraza et al., 2016). The instrument has a high reliability (k = 0.74). This scale has MMSE is a classical instrument for assessing cognitive domains, been reported in studies assessing psychopathology in AD including verbal memory, working memory, language, and (Zahodne et al., 2015) and other neurodegenerative conditions visuospatial functions. A score of 24 points has a sensitivity (Suárez-González et al., 2013). In addition, it is an instrument above 88.3% and a specificity close to 87% for detecting cognitive that has shown high sensitivity for detecting psychosis (Cohen- impairment in patients with neurodegeneration (Folstein et al., Mansfield and Golander, 2011) as well as depressive symptoms, 1975, 1983). sleep disturbances, eating changes and disinhibited conducts in TABLE 1 | Socio-demographic description of patients diagnosed with Alzheimer’s disease (AD) and frontotemporal degeneration (FTD). Gender AD (n = 47) FTD (n = 36) Male 20 (42.6%) 18 (50%) Female 27 (57.4%) 18 (50%) Variables Mean (SD) Median Mean (SD) Median Age at time 1 (years) 72.1 (7.3) 72 64.1 (6.4) 63.4 Age at time 2 (years) 74.9 (6.2) 75 67.6 (6.9) 65 Age difference (years) 2.6 (1.1) 2 2.4 (1.2) 2 Educational level (years) 13.6 (4.9) 14 14.4 (5.2) 15 Age at disease onset (years) 68.3 (6.9) 69 61.2 (6.6) 60 Note: SD, standard deviation; AD, Alzheimer’s disease; FTD, frontotemporal dementia. Frontiers in Aging Neuroscience | www.frontiersin.org 3 July 2019 | Volume 11 | Article 176 Santacruz Escudero et al. Neuropsychiatric Symptoms as Predictors in Neurodegeneration patients with neurocognitive disorders (Suárez-González et al., group of behavioral disturbances in a subsample of subjects 2013; Zahodne et al., 2015). in each group (see ‘‘Instrument’’ section for more information on the subsample of subjects who were studied using the NPI The Neuropsychiatric Inventory (NPI) measure). All statistical analyses were run using SPSS package A subsample of patients in AD group (n = 14) and FTD group version 21.0. (n = 14) were assessed using the NPI scale. This scale was used as a second measure to track behavioral disturbances in Disease Progression disease progression of neurodegenerative disorders. The NPI Previous studies have suggested that subjects who have a fall of (Cummins, 1997) consists of a selection of NPS and a measure more of four MMSE points per-year have rapidly progressive of severity of each symptom. The caregiver rates each of the cognitive deterioration (Doody et al., 2001, 2005). Based on this 12 symptoms as present or absent during the current month approach, we have subdivided the sample of each group (AD and, if some of those symptoms are present, they provide a and FTD) into subgroups according to the level of cognitive measure of severity (which is tracked using a Likert scale between deterioration. Thus, in each clinical group, we assessed the 1 and 3 points, with 1 being mild severity). The 12 symptoms on presence of subjects with expectable deterioration (subjects with the NPI include behavioral/conduct symptoms (aberrant motor a fall of less than four MMSE points per year) and a group behavior, disinhibition, apathy), emotional-mood symptoms with subjects with fast deterioration (subjects with a fall of more (euphoria, anxiety, depression, irritability), disruptive/psychotic than four MMSE points per year). Additionally, we assessed the symptoms (agitation, delusions, hallucinations) and other types presence of subjects without any level of deterioration (subjects of symptoms (nighttime behaviors, appetite and eating behavior in whom the MMSE did not change or even improved). In disturbances). This instrument has been previously reported each of the groups, we analyzed the relationship between the as efficient and reliable in tracking behavioral alterations in presence of NPS at the early stages of the disease and cognitive different neuropsychiatric disorders (Ismail et al., 2013, 2016) and functional decline. Additionally, we performed a one-way and neurocognitive disorders (Lai, 2014; Nowrangi et al., 2015; ANOVA to analyze the magnitude of NPS between subgroups Ismail et al., 2016). of disease progression in two groups of patients (FTD and AD). Data Analysis Mediation Analyses Demographic and neuropsychological data for the two groups of We also assessed whether demographic factors (age of disease patients (FTD and AD) were compared using one-way analysis onset and disease time), medical comorbidities (presence or of variance (ANOVA) and chi square tests for the categorical absence of comorbidities) and the usage of medications before variables. Where indicated, Tukey’s post hoc tests were used to diagnosis mediated the association between cognitive (1MoCA, examine group differences within neuropsychological measures. 1MMSE) and functional decline (1Lawton, 1Barthel) and Analyses of Longitudinal Progression Measures and scores of NPS tracked by CUSPAD. In addition, we assessed to Predictive Factors what extent the cognitive decline measures mediate effects on To calculate the degree of change in cognitive functioning and functional decline measures and vice versa. To this end, we ran instrumental and physical functionality between the first and an independent mediation analysis for each regression model of second stage of assessment, two progression indexes for cognitive cognitive and functional decline measures. performance 1MoCA (MoCA score at stage 1 − MoCA score at stage 2) and 1MMSE (1MMSE = MMSE score at stage 1 RESULTS − MMSE score at stage 2) were obtained. Following the same procedure, we obtained progression indexes for functionality, Results in cognitive, behavioral, and instrumental functionality 1Lawton and 1Barthel. measures in two stages of assessment are reported in Table 2 (see In order to assess the extent to which changes in NPS descriptive analyses in Table 2). FTD and AD groups differed predict a change in cognitive or instrumental measures in in age at disease onset (F (1,82) = 13.12, p < 0.001) as AD were both groups, we ran independent regression models in each older than FTD patients [AD = 68.6 years (SD = 8.2 years) and group using each of the above-mentioned progression indexes FTD = 60.7 years (SD = 7.5 years)]. Furthermore, FTD patients (i.e., 1MMSE, 1MoCA, 1Lawton and 1Barthel) as dependent reached higher levels of formal education than AD patients variables. Behavioral indexes tracked with CUSPAD (including [(F (1,82) = 11.54, p < 0.001; AD = 11.2 years (SD = 5.5 years) and a global score of CUSPAD obtained from sum total of each FTD = 14.8 years (SD = 6.2)]. No gender differences were found symptom of the scale) were included as independent variables in (X 2 (1) = 0.58, p = 0.62). each model in order to assess whether progression in one type of symptom predicts cognitive and functional progression. To First Stage of Assessment account for differences in educational level in the groups, we Analyses did not reveal differences between FTD and AD groups applied a covariance analysis to the regression models, adjusted in MoCA scores (F (1,82) = 0.65, p = 0.81; MoCA FTD = 17.3, independently for years of education (see Table 1). Effect sizes SD = 5.8, AD = 17.6, SD = 5.4) nor in MMSE scores (F (1,82) = 0.88, were calculated through partial eta-squared (η2 ). A group of p = 0.37; MMSE FTD = 23.1, SD = 4.9; AD = 22.9, SD = 4.8). similar analyses was run using the NPI scores and individual With respect to functionality and instrumental measures, no scores of each type of symptom as measures to track a broad differences were found between groups in the Lawton scale Frontiers in Aging Neuroscience | www.frontiersin.org 4 July 2019 | Volume 11 | Article 176 Santacruz Escudero et al. Neuropsychiatric Symptoms as Predictors in Neurodegeneration TABLE 2 | Cognitive performance. measures, analyses showed greater scores in the global score of Scales Mean SD CUSPAD in the FTD compared to AD (F (1,82) = 3.95, p < 0.05, η2 = 0.06). In addition, the FTD group compared with the AD (A) AD patients (n = 47) group showed higher scores in conduct problems (F (1,82) = 4.22, Cognitive measures MMSE, time 1 22.9 4.8 p < 0.05, η2 = 0.06) and in eating change measures (F (1,82) = 3.99, MMSE, time 2 19.8 5.7 p < 0.05, η2 = 0.06). In contrast, the AD group had higher scores MoCA, time 1 17.6 5.4 in sleep problems than in the FTD group (F (1,82) = 3.15, p < 0.05, MoCA, time 2 13.1 6.1 η2 = 0.06). No other comparisons reached significant values. Functionality measures Total Lawton, time 1 33.6 10.6 Second Stage of Assessment Total Lawton, time 2 24.2 9.2 Barthel Index, time 1 95.4 9.8 Analyses revealed minor MoCA and MMSE scores in FTD Barthel Index, time 2 87.8 9.9 compared with the AD group [for MoCA (F (1,82) = 2.93, p < 0.05, Neuropsychiatric symptoms η2 = 0.06; MoCA FTD = 12.5, SD = 5.4; AD = 13.1, SD = 6.1)], and CUSPAD, time 1 for MMSE (F (1,82) = 2.76, p = 0.05, η2 = 0.05; MMSE FTD = 15.6, Delusions 1.4 1.1 SD = 7.5; AD = 19.8, SD = 5.7). In addition, the AD group Hallucination 0.1 0.05 Illusion 0.2 0.06 showed greater impairment in functionality than the FTD group Conduct problems 1.4 1.1 as measured with the Lawton scale (F (1,82) = 2.75, p < 0.05, Depression 2.1 0.9 η2 = 0.05; Lawton FTD = 27.6, SD = 7.6; AD = 24.2, SD = 9.2). Sleep problems 1.8 1.2 No differences were observed in the Barthel index (F (1,82) = 1.92, Eating changes 0.5 0.07 p = 0.16; Barthel FTD = 87.2, SD = 7.1; AD = 87.8, SD = 9.9). With CUSPAD, time 2 Delusions 1.5 1.4 respect to behavioral measures, analyses showed higher scores in Hallucination 0.2 0.1 depressive symptoms in the AD group compared with the FTD Illusion 0.1 0.04 group (F (1,82) = 3.76, p < 0.05, η2 = 0.06). In addition, results Conduct problems 1.7 1.1 showed higher scores for eating changes in the FTD group when Depression 1.8 0.7 Sleep problems 1.1 0.6 compared with the AD group (F (1,82) = 3.94, p < 0.05, η2 = 0.06) Eating changes 0.7 0.1 and higher conduct problems (F (1,82) = 2.98, p < 0.05, η2 = 0.06). (B) FTD patients (n = 36) No other comparisons reached significant values. Cognitive measures MMSE, time 1 23.1 4.9 Progression Indexes MMSE, time 2 15.6 7.5 A progression index for each cognitive (1MMSE, 1MoCA) MoCA, time 1 17.3 5.8 and functional measure (1Lawton and 1Barthel) was created MoCA, time 2 12.5 5.4 Functionality measures as described above. Analyses between groups revealed greater Total Lawton, time 1 34.5 7.9 cognitive progression in FTD compared with the AD group Total Lawton, time 2 27.6 7.6 [1MoCA (F (1,82) = 3.43, p < 0.05, η2 = 0.06) and 1MMSE Barthel Index, time 1 94.2 7.8 (F (1,82) = 2.69, p < 0.05, η2 = 0.06)]. In addition, we observed Barthel Index, time 2 87.2 7.1 Neuropsychiatric symptoms a major functional progression in AD compared with the FTD CUSPAD, time 1 group [for 1Lawton (F (1,82) = 2.42, p < 0.05, η2 = 0.06)], and Delusions 1.9 0.8 no differences when we analyzed progression between groups in Hallucination 0.4 0.03 1Barthel (F (1,82) = 0.25, p = 0.51). Illusion 0.3 0.07 Conduct problems 2.5 1.4 Neuropsychiatric Symptoms and Depression 1.5 0.7 Sleep problems 1.2 1.3 Progression in Cognitive and Functional Eating changes 2.1 0.7 Measures CUSPAD, time 2 Delusions 1.8 1.1 AD Group Hallucination 0.3 0.2 Analyses Using CUSPAD Scale Illusion 0.2 0.09 We ran an independent regression model using 1MoCA as Conduct problems 2.6 0.8 dependent measure and the CUSPAD scores at the first stage Depression 1.1 0.8 Sleep problems 0.7 0.1 of assessment (scores for delusions, hallucinations, illusions, Eating changes 1.2 1.1 alterations, conduct problems, depressive and anxiety symptoms, Basic and instrumental functionality and neuropsychiatric symptoms in patients with AD sleep problems and eating changes) as independent measures. and FTD. Note: SD, standard deviation; AD, Alzheimer’s disease; FTD, frontotemporal This model reached significant values (F (1,46) = 4.21, p < 0.05, dementia; CUSPAD, Columbia University Scale for Psychopathology in Alzheimer’s R2 = 0.19), showing that the variability in 1MoCA was explained Disease; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment. by the presence of depression and the score for sleep alterations. No significant effects were observed when exploring the score for (F (1,82) = 0.95, p = 0.33; Lawton FTD = 34.5, SD = 7.9; AD = 33.6, other CUSPAD domains (see Table 3 for a further description of SD = 1.6) nor in Barthel index (F (1,82) = 2.11, p = 0.13; Barthel results). A similar regression model with 1MMSE as a dependent FTD = 94.2, SD = 7.8; AD = 95.4, SD = 9.8). Regarding behavioral measure of cognitive progression also reached significant values Frontiers in Aging Neuroscience | www.frontiersin.org 5 July 2019 | Volume 11 | Article 176 Santacruz Escudero et al. Neuropsychiatric Symptoms as Predictors in Neurodegeneration TABLE 3 | Independent regression model of cognitive progression (1MoCA and 1MMSE) and functional physical and instrumental progression (1Barthel and 1Lawton, respectively) through groups of symptoms of behavior disturbance with CUSPAD at first stage in patients with AD and FTD. Regression model Global Delusions Hallucinations Illusions Depression Conduct p. Sleep p. Eating p. (A) AD patients 1MoCA β = 0.82 β = 0.29 β = 0.01 β = 0.23 β = 0.48 β = 0.16 β = 0.45 β = 0.12 (F (1,46) = 4.21, p <0.05, P = <0.01 P = 0.19 P = 0.93 P = 0.22 P = <0.05 P = 0.31 P = <0.05 P = 0.34 R2 = 0.19) η2 = 0.12 η2 = 0.05 η2 = 0.01 η2 = 0.05 η2 = 0.09 η2 = 0.01 η2 = 0.09 η2 = 0.02 1MMSE β = 0.26 β = 0.25 β = 0.12 β = 0.19 β = 0.36 β = 0.04 β = 0.22 β = 0.16 (F (1,46) = 3.59, p <0.05, P = 0.11 P = 0.12 P = 0.49 P = 0.19 P = <0.05 P = 0.98 P = 0.13 P = 0.31 R2 = 0.09) η2 = 0.04 η2 = 0.01 η2 = 0.05 η2 = 0.05 η2 = 0.02 η2 = 0.03 η2 = 0.05 η2 = 0.05 1Lawton β = 0.11 β = 0.29 β = 0.26 β = 0.13 β = 0.33 β = 0.10 β = 0.18 β = 0.21 (F (1,46) = 3.71, p <0.05, P = 0.58 P = 0.09 P = 0.15 P = 0.34 P = <0.05 P = 0.54 P = 0.38 P = 0.12 R2 = 0.07) η2 = 0.05 η2 = 0.06 η2 = 0.05 η2 = 0.05 η2 = 0.07 η2 = 0.01 η2 = 0.05 η2 = 0.05 1Barthel β = 0.39 β = 0.25 β = 0.23 β = 0.16 β = 0.45 β = 0.21 β = 0.24 β = 0.03 (F (1,46) = 0.72, p = 0.51, P = <0.05 P = 0.19 P = 0.20 P = 0.21 P = <0.05 P = 0.23 P = 0.09 P = 0.81 R2 = 0.03) η2 = 0.09 η2 = 0.05 η2 = 0.05 η2 = 0.05 η2 = 0.12 η2 = 0.05 η2 = 0.06 η2 = 0.05 (B) FTD patients 1MoCA β = 0.36 β = 0.32 β = 0.11 β = 0.03 β = 0.078 β = 0.42 β = 0.14 β = 0.091 (F (1,35) = 7.28, p <0.001, P = <0.05 P = <0.05 P = 0.12 P = 0.56 P = 0.31 P = <0.001 P = 0.11 P = 0.25 R2 = 0.31) η2 = 0.12 η2 = 0.11 η2 = 0.04 η2 = 0.02 η2 = 0.04 η2 = 0.13 η2 = 0.04 η2 = 0.03 1MMSE β = 0.19 β = 0.15 β = 0.08 β = 0.05 β = 0.04 β = 0.18 β = 0.11 β = 0.09 (F (1,35) = 4.41, p <0.05, P = <0.05 P = 0.11 P = 0.22 P = 0.61 P = 0.78 P = 0.09 P = 0.11 P = 0.26 R2 = 0.12) η2 = 0.06 η2 = 0.05 η2 = 0.05 η2 = 0.02 η2 = 0.04 η2 = 0.06 η2 = 0.05 η2 = 0.05 1Lawton β = 0.91 β = 0.47 β = 0.02 β = 0.04 β = 0.21 β = 0.31 β = 0.04 β = 0.38 (F (1,35) = 3.12, p <0.05, P = <0.001 P = <0.05 P = 0.89 P = 0.81 P = 0.22 P = <0.05 P = 0.81 P = <0.05 R2 = 0.06) η2 = 0.16 η2 = 0.06 η2 = 0.05 η2 = 0.04 η2 = 0.05 η2 = 0.09 η2 = 0.03 η2 = 0.11 1Barthel β = 0.39 β = 0.11 β = 0.17 β = 0.03 β = 0.22 β = 0.41 β = 0.25 β = 0.21 (F (1,35) = 0.98, p = 0.47, P = 0.23 P = 0.54 P = 0.49 P = 0.88 P = 0.49 P = 0.11 P = 0.28 P = 0.33 R2 = 0.03) η2 = 0.06 η2 = 0.16 η2 = 0.02 η2 = 0.01 η2 = 0.02 η2 = 0.06 η2 = 0.05 η2 = 0.05 Note: AD, Alzheimer’s disease; FTD, frontotemporal dementia; CUSPAD, Columbia University Scale for Psychopathology in Alzheimer’s Disease; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment. (F (1,46) = 3.59, p < 0.05, R2 = 0.09). In this case, only the score for values (F (1,13) = 3.14, p < 0.05, R2 = 0.41), showing that the depression explained the variability of 1MMSE (Table 3A). variability of 1MoCA was explained by the score of depression A second group of regression models was run, including and the score for sleep disorders. No significant effects were 1Lawton and 1Barthel as dependent measures of functional observed when exploring the score for other NPI domains and instrumental progression and the CUSPAD total scores, (see Table 4B). A similar regression model with 1MMSE and scores in each symptom at first stage as independent as a dependent measure of cognitive progression and the measures. The model on 1Lawton reached significant values same independent measures did not reach significant values (F (1,46) = 3.71, p < 0.05, R2 = 0.07), showing that the variability (F (1,13) = 1.19, p = 0.09, R2 = 0.21). The regression models in 1Lawton was explained by the score for depression and the with 1Lawton as functional instrumental progression measure scores for sleep problems. The regression model with 1Barthel (F (1,13) = 1.25, p = 0.55, R2 = 0.28) and 1Barthel as functional as a dependent measure of functional physical progression and physical progression measure (F (1,13) = 0.97, p = 0.60, R2 = 0.24) using the same independent measures did not reach significant did not reach significant values (see Table 4A). values (F (1,46) = 0.72, p = 0.51, R2 = 0.03; see Table 3A). FTD Group Analyses Using NPI Analyses Using CUSPAD Scale In a subsample of subjects (n = 14), we used an extra scale We ran an independent regression model using 1MoCA as a for tracking NPS in order to analyze the role of a broad group measure of cognitive progression, and as independent measures of behavioral symptoms in predicting cognitive and functional we included the total score of CUSPAD and the scores in each progression in AD patients. We ran an independent regression group of symptoms of CUSPAD at the first stage. This model model using 1MoCA as a measure of cognitive progression, and reached significant values (F (1,35) = 7.28, p < 0.001, R2 = 0.31), as independent measures we included the total score of NPI, showing that the variability, 1MoCA was explained by the global and the scores in each group of symptoms of NPI at the first scores for CUSPAD, the score for delusions, the score for conduct stage (delusions, hallucinations, euphoria, depression, anxiety, problems and the score for eating changes (see Table 3 for a aggression, apathy, disinhibition, irritability, motor disturbance, further description of results). A similar regression model with eating changes, sleep problems). This model reached significant 1MMSE as dependent measure of cognitive progression and Frontiers in Aging Neuroscience | www.frontiersin.org 6 July 2019 | Volume 11 | Article 176 Santacruz Escudero et al. Neuropsychiatric Symptoms as Predictors in Neurodegeneration Note: AD, Alzheimer’s disease; FTD, frontotemporal dementia; NPI, neuropsychiatric inventory; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; Del., delusions; Hal., hallucinations; Euph., euphoria; Dep., P = < 0.05 the same independent measures also reached significant values η2 = 0.06) η2 = 0.05 η2 = 0.05 P = 0.39 P = 0.21 β = 0.40 β = 0.22 β = 0.38 Sle. P. (F (1,35) = 4.41, p < 0.05, R2 = 0.12; see Table 3B). In this case, only the global score of CUSPAD explained the 1MMSE variability. The regression model with 1Lawton as dependent measure of η2 = 0.05 η2 = 0.02 η2 = 0.04 functional and instrumental progression and CUSPAD scores as P = 0.21 P = 0.26 P = 0.69 β = 0.24 β = 0.24 β = 0.11 Eat. C. independent measures reached significant values (F (1,35) = 3.12, TABLE 4 | Significant Independent regression model of cognitive progression through groups of symptoms of behavior disturbance with NPI at first and second stage in patients with AD and FTD. p < 0.05, R2 = 0.06), showing that the global score of CUSPAD η2 = 0.03 and the scores for conduct problems explained the 1Lawton η2 = 0.02 η2 = 0.04 Mot. D. P = 0.65 P = 0.47 P = 0.42 β = 0.08 β = 0.12 β = 0.21 variability. The regression model with 1Barthel did not reach significant values (F (1,35) = 0.98, p = 0.47, R2 = 0.03; see Table 3B). Analyses Using NPI η2 = 0.06 η2 = 0.02 η2 = 0.04 P = 0.11 P = 0.31 P = 0.11 β = 0.31 β = 0.19 β = 0.26 In a subsample of FTD patients (n = 14), we assessed to Irr. what extent a broad group of behavioral symptoms predicted cognitive and functional progression using the NPI measure. The independent regression model using 1MoCA as a measure P = <0.05 η2 = 0.04 η2 = 0.08 η2 = 0.06 P = 0.59 β = 0.19 β = 0.48 β = 0.48 P<0.05 of cognitive progression, and the total score of NPI, and the Dis. depression; Anx., anxiety; Agg., aggression; Apa., apathy; Dis., disinhibition; Irr., irritability; Mot. D., motor disturbance; Eat. C., eating changes; Sle. P., sleep problems. scores in each group of symptoms of NPI at the first stage as independent measures reached significant values (F (1,13) = 2.41, p < 0.05, R2 = 0.39). In particular, this model showed that the variability of 1MoCA was explained by the score of P = <0.05 η2 = 0.05 η2 = 0.05 η2 = 0.04 P = 0.22 P = 0.12 β = 0.23 β = 0.43 β = 0.25 Apa. delusions, the score for disinhibition and the score for apathy. No significant effects were observed when exploring other NPI domains (see Table 4B). A similar regression model with 1MMSE as dependent η2 = 0.03 η2 = 0.05 η2 = 0.04 P = 0.82 P = 0.42 P = 0.11 β = 0.04 β = 0.17 β = 0.26 Agg. measure of cognitive progression and the same independent measures also reached significant values (F (1,14) = 2.19, p < 0.05, R2 = 0.30). In this case, the score of delusion and the disinhibition η2 = 0.04 η2 = 0.02 η2 = 0.03 P = 0.63 P = 0.89 P = 0.83 β = 0.11 β = 0.04 β = 0.04 explained the 1MMSE variability. No significant effects were Anx. observed when exploring other NPI domains. The regression models with 1Lawton as functional instrumental progression η2 = 0.07 η2 = 0.04 η2 = 0.05 measure (F (1,13) = 0.85, p = 0.65, R2 = 0.18) and 1Barthel as P = 0.47 P = 0.18 β = 0.44 β = 0.11 β = 0.29 P <0.05 Dep. functional physical progression measure (F (1,13) = 0.93, p = 0.57, R2 = 0.18) did not reach significant values (see Table 4B). η2 = 0.03 η2 = 0.03 η2 = 0.04 P = 0.65 P = 0.72 P = 0.11 β = 0.08 β = 0.09 β = 0.26 Regression Analyses According to the Euph. Subgroups of Disease Progression AD Group η2 = 0.04 η2 = 0.05 η2 = 0.03 P = 0.59 P = 0.39 P = 0.87 β = 0.19 β = 0.21 β = 0.03 Among the 47 AD patients, a total of three patients did not Hal. show deterioration (6.3% of the total of the sample), a group of 38 patients showed an expectable deterioration (85.1% of the total of the sample), and four patients showed fast deterioration (8.5% P = <0.05 P = <0.05 η2 = 0.04 η2 = 0.07 η2 = 0.06 P = 0.69 β = 0.09 β = 0.47 β = 0.56 of the total of the sample). Del. The analyses of NPS in AD subgroups only revealed differences in the depression scores at the first stage of assessment (F (1,46) = 6.56, p < 0.01). No differences were observed when η2 = 0.06 η2 = 0.05 η2 = 0.05 P = 0.10 P = 0.41 P = 0.39 β = 0.32 β = 0.15 β = 0.23 Global we analyzed the other symptoms (all p values above 0.3). A post hoc analysis (Tukey’s HSD, MS = 81.24, df = 46) revealed that patients who did not show deterioration presented minor depression scores compared to patients with expectable (B) FTD patients (n = 14) deterioration (p < 0.01) and patients with fast deterioration (A) AD patients (n = 14) 1MMSE (F (1,13) = 2.19, 1MoCA (F (1,13) = 3.14, 1MoCA (F (1,13) = 2.41, (p < 0.01). Additionally, patients with fast deterioration had p < 0.05, R2 = 0.39) p < 0.05, R2 = 0.41) p < 0.05, R2 = 0.30) Regression model major depression scores compared to expectable deterioration patients (p < 0.01). We ran new independent regression models only in the group of patients who presented the expectable deterioration (n = 38) to analyze the predictive role of NPS on cognitive Frontiers in Aging Neuroscience | www.frontiersin.org 7 July 2019 | Volume 11 | Article 176 Santacruz Escudero et al. Neuropsychiatric Symptoms as Predictors in Neurodegeneration and functional decline in the group of patients with expectable Mediation Analyses deterioration. The regression models on this group revealed a AD Group similar pattern of results to the regression models ran with We ran independent mediation analyses to track the impact the total number of patients. In particular, the model reached of demographical factors and medical comorbidities in the significant values (F (1,37) = 3.21, p < 0.05, R2 = 0.09), and showed association between cognitive (1MoCA, 1MMSE)-functional that the variability of 1MoCA was explained by the score for decline measures (1Lawton, 1Barthel) and NPS (tracked by depression (β = 0.39, p < 0.05, η2 = 0.06), the score for sleep CUSPAD). The regression model between 1MoCA (dependent problems (β = 0.35, p < 0.05, η2 = 0.06) and the global score of variable) and scores of CUSPAD (F (1,46) = 4.11, p < 0.05, CUSPAD (β = 0.55, p < 0.05, η2 = 0.06). The regression model R2 = 0.19) showed to be mediated by medical comorbidities, of the 1Lawton also reached significant values (F (1,37) = 2.99, age of disease, onset time of disease, 1Lawton and 1Barthel p < 0.05, R2 = 0.06) and revealed that the score for depression considering that the model remained significant although the (β = 0.31, p < 0.05, η2 = 0.06) and the scores for sleep problems F score decreased (F (1,46) = 2.19, p < 0.05, R2 = 0.05). The (β = 0.29, p < 0.05, η2 = 0.06) explained the variability of mediation analyses also revealed that comorbidities (β = 0.27, 1Lawton. The model of 1Barthel did not reach significant values p < 0.05, η2 = 0.06), age of disease onset (β = 0.29, p < 0.05, (F (1,37) = 0.72, p = 0.51, R2 = 0.03). We avoided running the η2 = 0.06) disease time (β = 0.49, p < 0.01, η2 = 0.07), 1Lawton regression model of 1MMSE, considering that MMSE scores (β = 0.52, p < 0.01, η2 = 0.07) and 1Barthel (β = 0.56, were used to categorize the subgroups of disease progression and p < 0.01, η2 = 0.07), explained the variance of the dependent then generate circularity. measure 1MoCA. However, no significant mediation effects were found when analyzing the usage of medications before FTD Group diagnosis (β = 0.11, p = 0.26, η2 = 0.02). Among the 36 FTD patients, three patients did not show A similar mediation analysis was run with the regression deterioration (8.3% of the total of the sample), a group of model of 1MMSE (F (1,46) = 3.59, p < 0.05, R2 = 0.09) and 29 patients showed an expectable deterioration (80.5% of the total revealed a partial mediation (the regression remained significant of the sample) and four patients showed fast deterioration (11.1% although the F index decreased) of comorbidities, age of disease of the total of the sample). The analyses of NPS in FTD subgroups onset and disease time (F (1,46) = 2.32, p < 0.05, R2 = 0.06). The only revealed differences in the conduct problems scores at the mediation analyses also revealed that comorbidities (β = 0.26, first stage of assessment (F (1,35) = 9.98, p < 0.01). No differences p < 0.05, η2 = 0.06), the age of disease onset (β = 0.31, p < 0.05, were observed when we analyzed other CUSPAD symptoms (all p η2 = 0.06), disease time (β = 0.41, p < 0.05, η2 = 0.06), 1Lawton values above 0.1). A post hoc analysis (Tukey’s HSD, MS = 81.24, (β = 0.58, p < 0.01, η2 = 0.07) and 1Barthel (β = 0.32, p < 0.05, df = 46) revealed that patients who did not show deterioration η2 = 0.06), explained the variability of 1MMSE. The usage of presented minor conduct problem scores compared to expectable medications before diagnosis did not reach significant mediation deterioration patients (p < 0.001) and fast deterioration patients effect (β = 0.003, p = 0.93, η2 = 0.01). (p < 0.0001). Additionally, patients with fast deterioration The mediation analyses on regression model of 1Lawton had major conduct problem scores compared to expectable (F (1,46) = 2.24, p < 0.05, R2 = 0.07) also revealed a partial deterioration patients (p < 0.05). mediation of comorbidities, age of disease onset and disease Following the same procedure used in the AD group, we time as revealed by the reduction of F scores in the model ran new independent regression models only in the group of (F (1,46) = 2.69, p < 0.05, R2 = 0.07). The mediation analyses also patients who presented the expectable deterioration (n = 29). As revealed that the presence of comorbidities (β = 0.29, p < 0.05, occurred in the AD group, the regression models on this group η2 = 0.06), the age of disease onset (β = 0.34, p < 0.05, η2 = 0.06), revealed a similar pattern of results to the regression models the disease time (β = 0.31, p < 0.05, η2 = 0.06), 1MoCA ran with the total number of patients. In particular, the model (β = 0.65, p < 0.01, η2 = 0.07) and 1MMSE (β = 0.53, p < 0.01, reached significant values (F (1,28) = 8.95, p < 0.001, R2 = 0.33) η2 = 0.07), explained the variability of 1Lawton. The usage of and showed that the global scores for CUSPAD, the score for medications before diagnosis did not reach significant mediation delusions (β = 0.44, p < 0.05, η2 = 0.06), the score for conduct effects (β = 0.005, p = 0.98, η2 = 0.01). problems (β = 0.48, p < 0.05, η2 = 0.06) and the score for eating The model of 1Barthel was initially non-significant changes (β = 0.42, p < 0.05, η2 = 0.06) explained the variability (F (1,46) = 0.72, p = 0.51, R2 = 0.03). The mediation analyses of 1MoCA. The regression model of the 1Lawton also reached did not reveal mediation effects of comorbidities age of disease significant values (F (1,28) = 3.12, p < 0.05, R2 = 0.06) and revealed onset, disease time and the usage of medication before diagnosis that the score for delusion (β = 0.45, p < 0.05, η2 = 0.06), the as the model remained non-significant after the inclusion of scores for conduct problems (β = 0.49, p < 0.05, η2 = 0.06) the comorbidities age of disease onset, disease time and cognitive score for eating changes (β = 0.39, p < 0.05, η2 = 0.06) and decline measures (1MMSE and 1MoCA; F (1,46) = 1.72, p = 0.08, the global score of CUSPAD (β = 0.62, p < 0.01, η2 = 0.09) R2 = 0.03). explained the variability of 1Lawton. The model of 1Barthel did not reach significant values 1Barthel (F (1,28) = 1.28, p = 0.29, FTD Group R2 = 0.05). We did not run the model of 1MMSE to avoid The mediation analyses on models of cognitive decline measures circularity considering that this measure was used to divide the [1MoCA (F (1,35) = 7.28, p < 0.001, R2 = 0.31) and 1MMSE subgroups of disease progression. (F (1,35) = 4.41, p < 0.05, R2 = 0.12)] revealed only a partial Frontiers in Aging Neuroscience | www.frontiersin.org 8 July 2019 | Volume 11 | Article 176 Santacruz Escudero et al. Neuropsychiatric Symptoms as Predictors in Neurodegeneration mediation of comorbidities, age of disease onset, disease time In our study, the sample of subjects in each group coursed and functional decline measures (1Lawton, and 1Barthel), as with an expectable pattern of disease progression (patients who showed by reductions in F scores [1MoCA (F (1,35) = 2.67, had a fall of around four MMSE points per-year). In the AD and p < 0.05, R2 = 0.31); and 1MMSE (F (1,35) = 2.44, p < 0.05, FTD groups, more than 80% of cases presented an expectable R2 = 0.12)]. The analyses revealed that comorbidities [1MoCA pattern of deterioration. (β = 0.33, p < 0.05, η2 = 0.06) and 1MMSE (β = 0.37, p < 0.05, Crucially, our results showed that subgroups of patients η2 = 0.06)], disease time [1MoCA (β = 0.44, p < 0.05, η2 = 0.06) according to the degree of disease progression also differed in and 1MMSE (β = 0.46, p < 0.05, η2 = 0.06)] and 1Lawton the magnitude of NPS symptoms at early stages of assessment. In [1MoCA (β = 0.37, p < 0.05, η2 = 0.06) and 1MMSE (β = 0.39, particular, in the AD group, the patients with fast and expectable p < 0.05, η2 = 0.06)] explained the variability of both cognitive deterioration presented at early stages of assessment major decline measures. The analyses on the mediation effect of age depressive scores compared to patients without deterioration. of disease onset [1MoCA (β = 0.05, p = 0.53, η2 = 0.05) and In the same line, the FTD patients with fast deterioration 1MMSE (β = 0.16, p = 0.17, η2 = 0.05)], Barthel [1MoCA and expectable deterioration showed major scores of conduct (β = 0.12, p = 0.22, η2 = 0.04) and 1MMSE (β = 0.08, p = 0.34, problems compared to patients with deterioration at early η2 = 0.05)] and the usage of medication [1MoCA (β = 0.06, stages of assessment. However, our results are far from being p = 0.92, η2 = 0.01) and 1MMSE (β = 0.12, p = 0.64, η2 = 0.01)] conclusive as we have few patients in the subgroup of fast did not reach significant effects. deterioration and the group without deterioration. Future studies The mediation analyses on the model of 1Lawton should explore the differences in NPS in subgroups of disease (F (1,35) = 2.89, p < 0.05, R2 = 0.06) revealed only partial progression by including more patients in each subgroup. The mediation effects due to comorbidities, age of disease onset Independent regression analyses only in the subgroup of patients and disease time as the regression models showed reductions with expectable deterioration revealed a similar pattern of results in F score (1Lawton (F (1,35) = 2.22, p < 0.05, R2 = 0.06). The as those observed in the total of sample in each group. This mediation analyses showed that the disease time (β = 0.44, pattern confirms that the results were reliable, and results p < 0.05, η2 = 0.06), 1MoCA (β = 0.34, p < 0.05, η2 = 0.06) were not due to out of range effects in subjects with atypical and 1MMSE (β = 0.31, p < 0.05, η2 = 0.06) explained the disease course. variability of 1Lawton. Additionally, analyses revealed that no Additionally, the impact of NPS at first stage of assessment on comorbidities (β = 0.13, p = 0.34, η2 = 0.04), no age of disease cognitive and functional decline was corroborated by a group of onset (β = 0.11, p = 0.39, η2 = 0.04) and no usage of medication extra analyses performed in a subsample of AD and FTD patients. before diagnosis (β = 0.07, p = 0.78, η2 = 0.01) reached significant By using the NPI (Cummins, 1997), a sensible instrument beta values to explain the variability of 1Lawton. to track a broad spectrum of behavioral alterations (affective The mediation analyses on 1Barthel did not reveal mediation changes, psychotic symptoms, anxiety symptoms, behavioral effects as the initial model between CUSPAD scores and control alterations, apathy, sleep disorders, eating changes and 1Barthel showed to be non-significant (F (1,35) = 0.98, p = 0.47, motor disturbances among others), we confirmed that the early R2 = 0.03) and remained non-significant after the inclusion behavioral alterations predict cognitive and functional decline. of comorbidities, age of disease onset, disease time, cognitive In agreement with the results found using the CUSPAD scores, decline measures and the usage of medications before diagnosis we observed that depression and sleep disorders tracked by NPI (F (1,35) = 0.44, p = 0.71, R2 = 0.01). predict cognitive decline in AD. This pattern of results affirms the preeminence of affective and somatic symptoms in predicting DISCUSSION a poor disease course in AD. Besides, in FTD, the presence of delusions, apathy and disinhibition tracked by NPI predict In this study, we have evaluated the role of the presence of cognitive decline. Crucially, with the usage of NPI, we were able NPS in predicting cognitive and functional decline in AD and to track two nuclear symptoms for FTD diagnosis (Zamboni FTD. Our results indicate that during the initial stages of et al., 2008; Rascovsky et al., 2011). Our results showed that apart disease, NPS affect in particular and differentiated ways, the from being crucial for diagnosis, those symptoms also have a role cognitive and functional disease progression for each type of in determining the disease course. neurocognitive disorder. In the case of AD, the results show that In agreement with previous studies, our results revealed the presence of depressive symptoms as well as sleep problems mediation effects of demographical factors (in particular age of had a higher predictive value for cognitive alterations than other disease onset and disease time; Borroni et al., 2008; Choi et al., NPS. In addition, the scores for depressive symptoms predict 2016) and comorbidities (Kansal et al., 2016; Eldholm et al., 2018) functional and instrumental progression. Conversely, the results on the association between NPS and cognitive and functional from the FTD group showed that the global scores of behavioral decline in both groups. However, the described pattern of alterations tracked by CUSPAD, the scores of delusions, conduct results in regression models remained significant after mediation problems and eating changes at early stages of assessment had a analyses, suggesting that the relationship between early NPI and higher predictive value for cognitive and functional progression. cognitive and functional decline are not completely explained by Together, our results highlighted the importance of tracking comorbidities and demographical factors. In addition, our results since early stages of disease assessment the presence of different showed a mutual mediation effect of cognitive and functional types of NPS, as those symptoms directly impact disease course. decline measures supporting previous studies revealing that Frontiers in Aging Neuroscience | www.frontiersin.org 9 July 2019 | Volume 11 | Article 176 Santacruz Escudero et al. Neuropsychiatric Symptoms as Predictors in Neurodegeneration both cognitive and functional measures are interdependent with no symptoms) predicted both severe dementia and death (Cornelis et al., 2017). (Rabins et al., 2013; Rosenberg et al., 2013), but this was not Concerning the potential factors that could mediate the discriminated by NPS, as it was done in our study. association between NPI and cognitive and functional decline Other studies have commented on having at least mild or measures, our study presents some limitations. First, although one clinically significant NPS at baseline (compared with no we found no mediation effects on cognitive and functional symptoms) and predicted both severe dementia and death (Peters disease progression related to the usage of medications et al., 2015; Rabins et al., 2013; Rosenberg et al., 2013), but this before diagnosis, we did not include further analysis on was not discriminated by NPS as was done in our study. the impact of pharmacological and non-pharmacological Using FDG PET, it is possible to determine that individuals interventions to alleviate NPS during the first and second with basic mild cognitive impairment with depressive symptoms stages of assessment on the cognitive-functional progression. have a higher load of B-amyloid with hypermetabolism in brain Previous studies have shown that pharmacological interventions, areas compared to non-depressive individuals (Ng et al., 2017). rehabilitation plans and person-centered interventions could This could be related to the presence of active inflammation, impact disease progression in both AD and FTD (Atri, 2011; resulting in a high-risk group for greater progression to a major Fazio et al., 2018). Future studies should assess to what extent neurocognitive disorder (Brendel et al., 2015). different pharmacological interventions could reduce the disease This could be related to the presence of active inflammation, progression in both AD and FTD. Second, we did not further resulting in a high-risk group for greater progression to a assess the mediation effect of different types of comorbidities on major neurocognitive disorder (Brendel et al., 2015). One cognitive and functional decline in neurodegenerative disorders. study reported that patients with depression in AD had more Previous studies have shown a strong impact of vascular medial temporal lobe atrophy (MTA) than patients with AD complications on cognitive and functional decline (Sena et al., without depression (Dhikav et al., 2014), and a post-mortem 2015; Janota et al., 2016). Future studies should control for both study revealed that AD patients with a history of depression AD and FTD the impact of comorbidities in generating and had more neuritic plaques and neurofibrillary tangles in the maintaining the NPI and to what extent a combination of those hippocampus than those without a history of depression factors accelerate the disease progression. (Rapp et al., 2008). Therefore, in patients with neurocognitive Previous studies have demonstrated the importance of disorders, depression could cause greater accumulation of depression in determining the progression towards a major β-amyloid, atrophy and inflammation leading to further neurocognitive disorder (Brendel et al., 2015; Zahodne et al., deterioration, as demonstrated by our findings. Therefore, in 2015; Kaup et al., 2016). A meta-analysis of 12 studies published patients with neurocognitive disorders, depression could cause in 2013 (Gao et al., 2013) showed that depression was a major greater accumulation of β-amyloid and inflammation, leading to risk factor for incidence of dementia (including AD, vascular further deterioration, as demonstrated by our findings. However, dementia and any dementia) and Mild cognitive impairment given that patients with depression experience alteration in (MCI). Our study adds new information on the role of different volition and motivation, it is not clear whether progression is types of NPS as predictors of the course of AD. The presence biased by depressive symptoms; in other words, it is not clear to of sleep problems predicted a worsening cognitive function in what extent alterations and cognitive and functional progression AD patients. Our results are in line with these studies, and also are explained by the fact that these patients have depressive indicate that sleep alterations at the first stages of disease could symptoms. Future studies should explore this further. Although also predict functionality impairments (Palmer et al., 2018). there is no consensus on the interaction between cognition Furthermore, when depressive symptoms and sleep problems are and affective symptoms in AD (Wilson et al., 2002; Rapp present during the first stages of AD, they are predictive of major et al., 2011), previous studies suggest that depression does affect impairments in instrumental functionality 2.5 years into disease progression at least in patients with mild cognitive impairment progression, which differs from other studies (Hallikainen et al., (Kaup et al., 2016). Our results agree with earlier findings 2018) in which delusions, agitation, and aberrant motor behavior that revealed the role of depression in predicting cognitive at the time of diagnosis predicted later AD progression. declining. Thus, emotional and affective reactions associated In addition, we demonstrate that the presence of depressive with the neuropathological changes may manifest as an affective symptoms in AD is associated with worse cognitive prognosis syndrome, signaling an impending decline in functional abilities (Teng et al., 2007). This is important, since it suggests that (Palmer et al., 2018). Our findings implied that depression specific monitoring of depression should have a greater value treatment might be applied to prevent or delay the occurrence in predicting deterioration in AD. Our findings differ from a and development of AD in patients with MCI. previous study (Peters et al., 2015), where NPS were predictors However, given that patients with depression experience of greater progression to severe neurocognitive disorder and alteration in volition and motivation, it is not clear whether death, and affective symptoms were associated with death only progression is biased by depressive symptoms; in other words, (Rabins et al., 2013). In addition, it also differs from other studies it is not clear to what extent alterations and cognitive and where psychotic symptoms, agitated behavior, and aberrant functional progression are explained by the fact that these motor behavior were associated with rapid disease progression patients have depressive symptoms. Future studies should (Buccione et al., 2007; Hallikainen et al., 2018). The presence of at explore this further. Although there is no consensus on the least mild or one clinically significant NPS at baseline (compared interaction between cognition and affective symptoms in AD, Frontiers in Aging Neuroscience | www.frontiersin.org 10 July 2019 | Volume 11 | Article 176 Santacruz Escudero et al. Neuropsychiatric Symptoms as Predictors in Neurodegeneration previous studies suggest that depression does affect progression functional profile in FTD. This scenario would agree with disease at least in patients with MCI (Kaup et al., 2016). Our results progression studies in FTD that show an increase and mixed are in agreement with earlier findings that revealed the role of pattern of NPS, and an association between NPS and prognosis depression in predicting cognitive declining. However, in our in this condition. Therefore, a broader exploration of the role study, the presence of depressive symptoms also impacts the of NPS in cognitive function in FTD, particularly whether NPS functionality. Although it is possible that functional impairments worsen the course of the disease or they are simply a consequence are directly related to cognitive decline, the role of depressive of the general frontotemporal neurocognitive alteration observed symptoms in explaining impairments in functionality could also in FTD, is needed. be associated with the fact that depressive symptoms also affect Furthermore, we observed that the presence of delusions volitional and motor skills, which are necessary for functional is predictive of cognitive impairment in FTD. Although autonomy. Altogether, our results show that it is of vital the presence of psychotic symptoms is more prevalent in importance to assess depressive symptoms more carefully in neurocognitive disorders associated with Lewy Bodies (Cagnin patients with AD. Our findings support the necessity for new et al., 2013; Gossink et al., 2017; Pezzoli et al., 2017), previous studies that evaluate whether an intervention on depression can studies have also reported that FTD patients could be affected modify the cognitive course of the underlying condition. by delusions (Gossink et al., 2017). Delusions are especially Previous studies have reported a high prevalence of pertinent as they are less widely recognized as harbingers of sleep alterations in different neurodegenerative disorders structural brain disease and more likely to lead to psychiatric (Mander et al., 2016). In fact, a possible association between misdiagnosis. Delusion mechanisms are likely to involve neural behavioral pathways that include sleep alterations and networks in the frontal and temporal lobes that are particularly neuropathological changes was recently demonstrated vulnerable in FTD (Omar et al., 2011). Our results also reveal that (Ehrenberg et al., 2018). Sleep-wake disturbances have been a major presence of delusions could be a bio-behavioral predictor associated with the formation of amyloid plaques, and with the of cognitive decline in FTD (Mendez et al., 2008). accumulation of the amyloid-β (Aβ) peptide (Lim et al., 2014). Finally, results in the FTD group also demonstrate that Our results are in line with these studies, and also indicate that the presence of eating changes at the first stage of disease sleep alterations at the first stages of disease could also predict predicts cognitive and functional impairments in these patients. functionality impairments (Palmer et al., 2018). Eating abnormalities including appetite changes, increased The presence of higher global scores in the scale tracking carbohydrate craving, and changes in food preference are present different types of NPS (CUSPAD), along with conduct problems in up to 60% of patients with frontotemporal dementia (FTD), and delusions predicts a worsened progression of the cognitive and are one of the core symptoms required for the diagnosis of state and functionality in the FTD group. The role of NPS in FTD behavioral variant FTD (bvFTD; Rascovsky et al., 2011; Ahmed has shown to be nuclear and constituted of an accurate diagnosis et al., 2015, 2018). Arguably, eating behavior alterations in FTD for a behavioral variant of FTD, but also in linguistic variants could be explained by altered frontal and temporal lobe volume, (Gorno-Tempini et al., 2011; Rascovsky et al., 2011). Conduct as well as impairments in networks linking those structures to problems, in particular those related to apathy and disinhibition, the striatum and orbitofrontal cortices (Ahmed et al., 2018). are present from the very early stages of disease and many times Crucially, the impairments in these fronto-temporal and insular in prodromes (Bott et al., 2014). In addition, it has recently been networks are at the core of behavioral and cognitive alterations in reported that the type of the first symptom in FTD, in particular FTD. Our results indicate that the presence of eating changes at the predominant presence of apathy or disinhibition, is related to the first stages of disease could be a sensitive bio-behavior marker a particular pattern of neurocognitive impairment (Santamaría- of cognitive and functional impairment in FTD. García et al., 2016). In this study, we add new data on the role Conduct problems and delusions are related to changes in of NPS in FTD by showing that the progression of a mixed frontotemporal and insular networks (Ibañez and Manes, 2012), group of NPS (general alteration of NPS and particularly, the and one might argue that eating changes could be considered presence of conduct problems) leads to a worse cognitive and as initial clinical footprints of the classical neurocognitive functional prognosis. impairment pathway reported in FTD. Contrary to what we observed in AD, depression is not a Our findings support the need for further studies exploring strong predictor for cognitive and functional progression in the differential role of various types of symptoms in predicting FTD. Poor control of behavior in general could be explained cognitive and functional changes in neurocognitive disorders. by a pattern of classic neurocognitive alterations in FTD, In particular, it is important to elucidate the role of apathy, characterized by alterations in key structures for behavioral disinhibition and irritability in predicting the general course of regulation, including frontal, temporal, and insular structures the disease progression, with the presence of particular pathways (Ibañez and Manes, 2012; Baez et al., 2017). These findings could of neural atrophy and cognitive impairments of neurocognitive also suggest that NPS are another face of the neurocognitive disorders. Similarly, it is essential to refine techniques for the degeneration seen in FTD. In this sense, a progression of observation and measurement of NPS during the diagnostic cognitive, functional, and behavioral alterations in FTD is process, as well as in the follow-up of neurocognitive disorders. generated by classic neurocognitive changes in this condition. To this effect, it is necessary to include information provided Another explanation to be explored in future studies is whether by family members, companions, and caregivers, as well as the the presence of NPS generates a worsening of the cognitive and assessment of NPS clinicians, in order to improve symptom Frontiers in Aging Neuroscience | www.frontiersin.org 11 July 2019 | Volume 11 | Article 176 Santacruz Escudero et al. Neuropsychiatric Symptoms as Predictors in Neurodegeneration evaluation. Taken together, our results highlight the need multidimensionality and false positives by using effect sizes to better and more closely monitor NPS in neurocognitive and post hoc analyses of each contrast when it was appropriate. disorders, along with studies that can determine if the presence of Future studies should assess the multidimensionality of NPS can have a generative (causal) role in cognitive alterations. behavioral alterations in disease progression of AD and FTD by If so, new studies should also consider whether an effective using another statistical approach including multidimensional treatment of behavioral disturbances would change the clinical reduction following principal component analyses or machine course of these conditions. learning methods. Our results might be elucidating several aspects of the same problem. It is well known that changes in behavior are associated CONCLUSION with changes in cognition and functionality. In some cases, cognitive alterations are found in patients without behavioral In this study, we demonstrate that the progression of behavioral alterations and may be a predictive factor. Despite this, our disturbances is a determining factor in predicting functional and study shows that behavioral progression is a determining factor cognitive deterioration in patients. In particular, we observed that should be monitored and evaluated when analyzing the that the presence of general behavioral alterations, delusions progression of neurocognitive disorders. and eating changes predicts functional and cognitive impairment Therefore, NPS are much more than specifiers in in FTD. In contrast, in patients with AD, the progression of neurocognitive disorders and are likely to play a central depression as well as sleep changes are two crucial behavioral role in neurodegenerative diseases. The results of our study alterations that predict changes in the course of the condition. also support further studies to establish whether there are Taken together, our results highlight the importance of detecting neurocognitive biomarkers associated with the progression of and monitoring NPS in patients with different types of NPS in neurocognitive disorders and to evaluate the impact neurocognitive disorders. that adequate treatment and control of NPS can have on the functional and cognitive progression of these pathologies. ETHICS STATEMENT Analyses in the subsample of AD patients assessed with NPI revealed that depressive but not anxiety symptoms significantly Participants in this study provided verbal informed consent to predict cognitive decline. This pattern of results is in agreement be enrolled in this study. All patient caregivers provided written with results reported with the CUSPAD. Contrary to the informed consent according with the Helsinki declaration. CUSPAD, the NPI is more selective in tracking particular types This study was approved by The Ethics Committee of the of symptoms. Although in our study the assessment with NPI Pontificia Universidad Javeriana and the Hospital Universitario revealed significant predictor effects for depressive symptoms, it San Ignacio in Bogotá (Colombia). Additionally, we ran a is unclear to what extent the negative results for other behavioral secondary analysis of the information obtained in clinical records symptoms are due to a restricted number of subjects assessed of patients. In particular, we assessed the scores of the results of with this instrument. Future studies should assess the impact NPI from that clinical records. All information obtained of the of behavioral symptoms on cognitive and functional decline by clinical records were treated ensuring confidentiality and privacy using different types of measures able to track a broader profile of identification information. of behavioral, affective and cognitive symptoms. In addition, it would be useful to assess the predictive role AUTHOR CONTRIBUTIONS on cognitive and functional decline in neurodegeneration of other cognitive and psychological factors, including the copying JSE and HS-G participated in design and conceptualization styles, problem solving skills and personality traits, which of the study, data acquisition, analysis and interpretation of have beeb shown to be relevant factors in predicting disease the data, writing and revision of the manuscript. JB and ÁP course in neurodegenerative disorders (Irish et al., 2012a,b; participated in the data acquisition, data analysis and revision D’Iorio et al., 2018). of the manuscript. DM, PR and VP-S participated in the design In this study, we have tried to fully analyze to what extent and conceptualization of the study and provided revisions of the a broad group of behavioral symptoms could impact different manuscript. All authors contributed equally in the preparation of cognitive and functional decline measures. A potential limitation the manuscript. The manuscript was approved by all coauthors. of our study is that we have tested different regression models with a considerable number of predictors and outcomes. FUNDING Evidently, the presence of a major number of factors and levels of analyses could increase error rates and false positive effects. This work was partially supported by grants from the Centro However, we considered that there are some attenuators for this de Memoria y Cognition Intellectus, Hospital Universitario San issue. First, we were interested in assessing the impact of NPS on Ignacio and Javeriana University. disease progression following an approach that did not follow any a priori assumptions on NPS associated to disease progression. ACKNOWLEDGMENTS In this sense, the inclusion of variables of levels of analyses were needed to maintain the independence of assumptions We wish to thank the patients and their families who kindly in this topic. Second, we have tried to control the effects of contributed with this study. Frontiers in Aging Neuroscience | www.frontiersin.org 12 July 2019 | Volume 11 | Article 176 Santacruz Escudero et al. Neuropsychiatric Symptoms as Predictors in Neurodegeneration REFERENCES Dhikav, V., Sethi, M., and Anand, K. S. (2014). Medial temporal lobe atrophy in Alzheimer’s disease/mild cognitive impairment with depression. Br. J. Radiol. Ahmed, R. M., Irish, M., Kam, J., van Keizerswaard, J., Bartley, L., Samaras, K., 87:20140150. doi: 10.1259/bjr.20140150 et al. (2018). 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Neuropsychiatric disturbances in Alzheimer’s disease: what have we learned from neuropathological studies? Curr. Copyright © 2019 Santacruz Escudero, Beltrán, Palacios, Chimbi, Matallana, Alzheimer Res. 13, 1145–1164. doi: 10.2174/156720501366616050 Reyes, Perez-Sola and Santamaría-García. This is an open-access article distributed 2123607 under the terms of the Creative Commons Attribution License (CC BY). The use, Velakoulis, M., Walterfang, M., Mocellin, R., Pantelis, C., and McLean, C. (2009). distribution or reproduction in other forums is permitted, provided the original Frontotemporal dementia presenting as schizophrenia-like psychosis in young author(s) and the copyright owner(s) are credited and that the original publication people: clinicopatho-logical series and review of cases. Br. J. Psychiatry 194, in this journal is cited, in accordance with accepted academic practice. No use, 298–305. doi: 10.1192/bjp.bp.108.057034 distribution or reproduction is permitted which does not comply with these terms. Frontiers in Aging Neuroscience | www.frontiersin.org 15 July 2019 | Volume 11 | Article 176