Neuropsychiatric or Behavioral and Psychological Symptoms of Dementia (BPSD): Focus on Prevalence and Natural History in Alzheimer's Disease and Frontotemporal Dementia

Neuropsychiatric or behavioral and psychological symptoms of dementia (BPSD) represent a heterogeneous group of non-cognitive symptoms that are virtually present in all patients during the course of their disease. The aim of this study is to examine the prevalence and natural history of BPSD in a large cohort of patients with behavioral variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) in three stages: (i) pre-T0 (before the onset of the disease); (ii) T0 or manifested disease (from the onset to 5 years); (iii) T1 or advanced (from 5 years onwards). Six hundred seventy-four clinical records of patients with bvFTD and 1925 with AD, from 2006 to 2018, were studied. Symptoms have been extracted from Neuropsychiatric Inventory (NPI) and from a checklist of BPSD for all periods observed. In our population, BPSD affect up to 90% of all dementia subjects over the course of their illness. BPSD profiles of the two dementia groups were similar but not identical. The most represented symptoms were apathy, irritability/affective lability, and agitation/aggression. Considering the order of appearance of neuropsychiatric symptoms in AD and bvFTD, mood disorders (depression, anxiety) come first than the other BPSD, with the same prevalence. This means that they could be an important “red flag” in detection of dementia. With the increase of disease severity, aberrant motor behavior and wandering were significantly more present in both groups. Differences between BPSD in AD and bvFTD resulted only in prevalence: Systematically, in bvFTD, all the symptoms were more represented than in AD, except for hallucinations, depression, anxiety, and irritability. Given their high frequency and impact on management and overall health care resources, BPSD should not be underestimated and considered as an additional important diagnostic and therapeutic target both in patients with AD and bvFTD.

1 Association for Neurogenetic Research (ARN), Lamezia Terme, Italy, 2 Regional Neurogenetic Centre -ASP-CZ, Lamezia Terme, Italy, 3 Department of Mathematics and Computer Science, University of Calabria, Rende, Italy, 4 Neurology Unit, Fondazione Istituto Giglio, Cefalù, Italy, 5 Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy, 6 Department of Internal Medicine, Pugliese Ciaccio Hospital, Catanzaro, Italy, 7 Department of Biology, Ecology and Earth Sciences, University of Calabria, Rende, Italy Neuropsychiatric or behavioral and psychological symptoms of dementia (BPSD) represent a heterogeneous group of non-cognitive symptoms that are virtually present in all patients during the course of their disease. The aim of this study is to examine the prevalence and natural history of BPSD in a large cohort of patients with behavioral variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) in three stages: (i) pre-T0 (before the onset of the disease); (ii) T0 or manifested disease (from the onset to 5 years); (iii) T1 or advanced (from 5 years onwards). Six hundred seventy-four clinical records of patients with bvFTD and 1925 with AD, from 2006 to 2018, were studied. Symptoms have been extracted from Neuropsychiatric Inventory (NPI) and from a checklist of BPSD for all periods observed. In our population, BPSD affect up to 90% of all dementia subjects over the course of their illness. BPSD profiles of the two dementia groups were similar but not identical. The most represented symptoms were apathy, irritability/affective lability, and agitation/aggression. Considering the order of appearance of neuropsychiatric symptoms in AD and bvFTD, mood disorders (depression, anxiety) come first than the other BPSD, with the same prevalence. This means that they could be an important "red flag" in detection of dementia. With the increase of disease severity, aberrant motor behavior and wandering were significantly more present in both groups. Differences between BPSD in AD and bvFTD resulted only in prevalence: Systematically, in bvFTD, all the symptoms were more represented than in AD, except for hallucinations, depression, anxiety, and irritability. Given their high frequency and impact on management and overall health care resources, BPSD should not be underestimated and considered as an additional important diagnostic and therapeutic target both in patients with AD and bvFTD.

INTRODUCTION
Dementia is an insidious syndrome characterized by the progressive decline of mental functions. In addition to cognitive deficits, at least 90% of patients exhibit various neuropsychiatric or behavioral and psychological symptoms of dementia (BPSD) at any given point in the course of their illness (1). BPSD can be defined as a wide range of non-cognitive symptoms involving perception (e.g., hallucinations), mood (e.g., depression, anxiety), behavior (e.g., aggression, disinhibition), personality, and basic functioning (2)(3)(4)(5)(6). The pathogenesis of these symptoms is not still completely understood, and the current knowledge supports multifactorial causes, involving the interaction of biological, psychological, and social factors (7). It has been shown that BPSD are associated with high levels of distress both in dementia sufferers and their caregivers, as well as with adverse outcomes, long-term hospitalization, and misuse of medications and increased use of health care resources (8)(9)(10)(11)(12). Thus, in addition to cognitive deterioration, BPSD are a relevant and meaningful clinical target for intervention (13) although are still now considered as non-disease-specific markers (14). Despite the importance of these symptoms in both clinical characterization and prognosis of dementia, the few studies performed on their natural history and prevalence achieved mixed results (15)(16)(17)(18)(19)(20). However, previous studies suggest that some of these symptoms are more predominant in one type of dementia than in another (15). Instead, understanding the full course of BPSD in different forms of dementia might be important to guide treatment choices and to improve the quality of life of both patients and their caregivers. In particular, we decided to focus our attention on the comparison of prevalence and natural history of BPSD between Alzheimer's disease-the most prevalent form of senile dementia (21)-and the behavioral variant of Fontotemporal Dementiathe most common form of presenile dementia (16).

Alzheimer's Disease (AD) and BPSD
Alzheimer's disease (AD) is the most widespread neurodegenerative disorder worldwide (20)(21)(22), typically characterized by memory loss and other cognitive deficits (20,23). BPSD are being increasingly recognized as common serious problems in AD (8). Several findings suggest that some BPSD-i.e., depression, anxiety, and apathy-can occur before the onset of cognitive decline in AD (8,24,25) and could predict both cognitive decline and progression from MCI to AD (26). On the other hand, it has been reported an onset of BPSD several months after AD diagnosis (27). Conflicting results were also obtained about the prevalence of BPSD. Several findings showed that apathy is the most common BPSD in AD (20,28,29).
Conversely, other studies indicated sleep disturbances (17), irritability/aggression (18), or depression (30) as the most prevalent BPSD in AD. These discordant findings stress the urgency to better characterize the prevalence and natural history of BPSD in AD.

Frontotemporal Dementia (FTD) and BPSD
Frontotemporal dementia (FTD) is the most frequent neurodegenerative disorder with a presenile onset (16,31). Based on clinical presentation, there are three main clinical syndromes of FTD: (i) behavioral variant FTD (bvFTD); (ii) non-fluent primary progressive aphasia (PPA); (iii) and semantic variant primary progressive aphasia (svPPA) (32). bvFTD represents the most frequent clinical picture of FTD (33) and is the only neurodegenerative disorder that requires the presence of behavioral changes to establish the diagnosis (32). These symptoms include disinhibition, apathy, hyperorality, and dietary changes (34). However, it has been shown that most people with FTD also show psychotic symptoms, such as delusions or hallucinations (35), resembling schizophrenia, major depressive and bipolar spectrum disorders (16,36). On the other hand, Mendez et al. (19) documented an infrequency of psychotic symptoms in patients with bvFTD. Compared to patients with AD, Mukherjee et al. (15) reported a higher frequency of delusions and a low frequency of hallucinations (15), whereas Mendez et al. (37), a lower frequency of both delusions and hallucinations in bvFTD. These contradictory findings highlight the need to better understand the prevalence and natural history of BPSD in bvFTD and to make a comparison with patients with AD, in particular for psychotic symptoms.

THE CURRENT STUDY
The aim of this retrospective study was to examine the prevalence and to compare the natural history of BPSD in a large cohort of patients with AD and bvFTD. More specifically, we wished to establish the frequency and type of BPSD in relation to the onset of these two types of dementia.

Participants and Procedure
The study population included 2,599 patients with bvFTD and AD (950 men and 1,649 women), followed at the Regional Neurogenetic Centre (ASP CZ) from 2006 to 2018. Diagnosis was performed according to criteria of The Lund and Manchester Groups Englund et al. (38) and Rascovsky et al.
(32), NINCDS-ADRDA criteria (39), and National Institute on Aging and Alzheimer's Association workgroup (40). Data were retrospectively extracted from the respective medical records on the basis of completeness of clinical data. Inclusion criteria were: (1) Diagnosis of probable AD or bvFTD according to the above-mentioned criteria; (2) Availability of a reliable caregiver; (3) Completeness of clinical data; (4) Patients free from pharmacologic treatments for BPSD. Exclusion criteria were: (1) Patients with a past history of psychiatric illness and/or any neurological illness that could interfere with neuropsychological tests; (2) Unavailability of a reliable caregiver; (3) Incompleteness of clinical data; (4) Known or suspected history of alcoholism or drug abuse. Most of the patients were from Southern Italy. As this paper focuses on natural course of BPSD in dementia, we identified the moment in which the BPSD appeared in the history of the disease: (i) pre-T0 (before the onset of the disease); (ii) T0 or manifested disease (from the onset to 5 years); (iii) T1 or advanced (from 5 years onwards).

bvFTD Cohort
The bvFTD sample included 674 patients (317 men and 357 women). Their mean age was 66.7 ± 11.1 years. The mean followup was 2.6 years ± 2.8, and the first clinical observation was 4.6 ± 4.3 years after the onset of the symptoms (ETOV: Elapsing Time between Onset and first Visit).

AD Cohort
The AD sample included 1,925 patients (1,292 women and 633 men). Their mean age was 71.5 ± 8.9 years, the mean follow-up was 3.5 ± 2.9 years, and ETOV was 3.7 ± 3.2 years.

MEASURES
A detailed anamnesis and clinical history were collected to identify the first core signs experienced by the patients or observed by family that could be identified as the moment of the onset of dementia. Exhaustive information was also collected for the time preceding the onset of dementia. We also analyzed data from the following examinations that are routinely performed in our Center at the first visit and every 6 months in all patients:

Statistical Analysis
All analyses were performed with SPSS statistical software 21 (SPSS Inc., Chicago, IL, USA). Descriptive statistics, frequencies, contingency coefficient test (cross tabs) were evaluated to analyze prevalence and occurrence of BPSD. For the analysis of dichotomous variables between two groups, a chi-square  Table 1 reports the comparison of the demographic and clinical characteristics of the two groups (AD and bvFTD). Female gender (p < 0.001), late onset (p < 0.001), and low education (p < 0.001) were more represented in AD compared to the bvFTD group. Patients with AD also arrive to the first clinical consultation before patients with bvFTD (ETOV) (p < 0.001).

RESULTS
On the CDR, both groups showed a slight/moderate dementia (AD < bvFTD), with patients with AD being more autonomous (on ADL and IADL, p < 0.001; p < 0.001), and more aware about their clinical status (CIRS) (p < 0.001) than patients with bvFTD.

Natural History of BPSD
Considering the mean (in years) of the onset of BPSD in relation to the onset of dementia, most BPSD were identified at T0, but some signs were also identified at pre-T0 and T1. Depression was the first appearing BPSD, followed by apathy and anxiety in bvFTD and anxiety and apathy in AD (Figure 2). In patients with bvFTD, depression became obvious 0.5 years before the onset of dementia, while, in AD, was reported at 1.08 years after the onset of dementia. The BPSD that significantly appear first in AD compared to patients with bvFTD were: depression (p = 0.002), apathy (p < 0.001), hallucinations (p = 0.001), agitation/aggression (p = 0.018), and disinhibition (p < 0.001) (Table 4, Figure 2).

DISCUSSION
BPSD are very common, nearly invariable, and are associated with high levels of distress in both dementia sufferers and their caregivers. In our study, we examined the prevalence and the timing of BPSD in a sample of 2,599 patients with AD and bvFTD. Our results confirm that, during the natural course of dementia, BPSD can be subjectively experienced by the patients and/or reported by the caregivers. We found that BPSD were present in over 90% of the whole cohort, more specifically in 96.4% in bvFTD and 90.8% in AD cohorts over the course of their illness. Apathy was the most represented symptom in both diseases (61.9% of the entire sample) in agreement with previous studies (3,48,49). Interestingly, in patients with bvFTD, apathy was the most frequent symptom throughout the whole course of the disease. These data are in agreement with Kumfor et al. (49) who found that 60% of patients with AD and 84% of patients with bvFTD had apathy, and it was more severe and frequent in patients with bvFTD. About patients with AD, we found that depression and apathy were the most frequent symptoms in the early phases of the disease and agitation in the late ones. These data confirm that depression and apathy could represent a wakeup call to which clinicians should pay attention for the early detection of AD (26). However, delusions and hallucinations were also present in a consistent percentage in both patients with AD and bvFTD. This is an interesting finding, as these psychotic symptoms have not been systematically reported as part of the clinical FTD (32, 50) and AD (39,40) criteria. Based on previous studies, in general, psychotic symptoms were considered quite rare in FTD compared to other dementia diseases, and, only recently, some studies have found a higher proportion of patients with psychotic features as part of their FTD symptomatology. Landqvist Waldö et al. (35) found that psychotic symptoms were present in 32% of their FTD neuropathologically verified sample, while Legarde and Sarazin (51) found a frequency of 20%. Considering the timing of the onset of BPSD in AD and bvFTD, most of these symptoms had the onset within 5 years from the onset of dementia. However, some BPSD appeared after 5 years and, in FTD, even before the onset of dementia. Mood disorders (depression, anxiety) had an earlier onset compared to other BPSD, with the same frequency in both dementias. In particular, depression was the first symptom that, in bvFTD, a sample could already be observed before the onset of the Frontiers in Neurology | www.frontiersin.org disease (the mean of the year of the onset of depression is 0.5 year before the onset of cognitive sympthoms). Many studies explored the temporal relationship between depressive symptoms and cognitive impairment (52,53), suggesting that depression could be able to predict dementia and that mood disorders may be an important "red flag" in the detection of neurocognitive impairment and people should learn to recognize them to reach a prompt diagnosis. This may explain why, in our patients, the time elapsed between the onset of symptoms of dementia, and the first visit was delayed (around 4 years). The diagnostic delay (54) may be due to the fact that initial signs of cognitive impairment or deflection of mood in elderly people is considered to be normal, and they may arrive to a clinical consultation only when the concern for their cognitive and behavioral symptoms has become more serious for the patients and/or the families. This study has potential limitations. Firstly, the different patterns of BPSD that we observed between patients with AD and patients with bvFTD can be related to several genetic risk factors, brain's pathophysiological changes, gender differences, drugs usage, and the different neurobiological profiles of the two pathologies. Indeed, further studies are needed to correlate genetic risk factors with the manifestation of BPSD, as well as to analyze the different patterns of BPSD and brain functional changes across the course of the disease in AD and bvFTD, taking into account gender differences and drugs. Secondly, NPI is a broad-spectrum screening test. In future researches, it may be useful to administer more specific tests for some symptoms, such as geriatric depression scale (GDS) and apathy evaluation scale (AES). Third, several associations appear to be weak, albeit with an alpha value over the significance threshold.

CONCLUSION
BPSD profiles of the two groups were similar but not identical. An early and correct identification and evaluation of BPSD are challenges and crucial parts in the clinical approach and management of these disorders. As at the disease onset, BPSD may dominate the clinical picture and may be interpreted as a Data are presented as mean and standard error (in parenthesis). *Significant difference (p < 0.05). **Significant difference (p < 0.001).
primary psychiatric disorder, this can delay the proper evaluation and diagnosis of dementia (55). This is an important point as the earlier diagnosis is reached; more families and patients will be able to benefit from the use of appropriate clinical support and possible intervention. Because of their high frequency and impact on management and overall health care resources, BPSD should not be underestimated and be considered as an additional important diagnostic and therapeutic target both in patients with AD and patients with bvFTD. In conclusion, from a qualitative point of view, mood disorders were more often seen in the preclinical phase and/or in the first years of dementias in our cohort, while motor behaviors (aberrant motor activity and wandering) tended to occur in the later stages, generally after 5 years from the onset. This sequence was found in both diseases, and the main difference in BPSD between FTD and AD was quantitative and mainly related to their frequencies, being more represented in FTD than in AD.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ETHICS STATEMENT
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.