Psychosis in Neurodegenerative Dementias: A Systematic Comparative Review

Prevalence

Psychosis is a frequently observed phenomenon during the course of ND, with reported prevalence ranging from 22.5% to 54.1% in AD, 55.9% to 73.9% in DLB, and 18% to 42% in FTD (Supplementary Table 2). Among the various ND subtypes, DLB consistently exhibits the highest incidence of psychotic symptoms, while subjects with sporadic FTD tend to present the lowest incidence [32, 33]. Regrettably, there is a scarcity of epidemiological data regarding psychosis at the early stages of neurodegenerative diseases and no prevalence could be derived from the literature.

Potential risk and protective factors

The age at onset of AD has been correlated with the incidence of psychosis as the first behavioral symptom, a cohort study of 7,815 patients having shown a higher prevalence (7%) after 79 years compared to before 60 years (3%) [34]. On the other hand, a younger age at onset was reported to be associated with an increased risk of misdiagnosis of PPD in patients with ND-related psychosis [16].

Family psychiatric history was identified as a potential risk factor for psychotic symptoms in FTD, affecting approximately 26.6% of a cohort of 97 patients with pathologically-confirmed FTD [16].

Genetics also play a significant role in the occurrence of psychosis in FTD patients, with a notable association observed with the C9Orf72 mutation (21). Indeed multiple cases have been reported in the literature where patients initially presenting with prominent psychosis were later found to carry this mutation [3, 35].

Generalities

Delusions, characterized by false beliefs based on incorrect inferences about external reality or oneself resistant to contradictory evidence [1], commonly occur during the course of ND. The prevalence of delusions varies across studies, ranging between 5.82% and 51.2% in AD [2, 36–39], 32.8% and 60.9% in DLB [2, 39–41], and 10.5% and 34.8% in FTD, with higher incidence reported in FTD patients with TDP-43 pathology [2, 43] (Supplementary Table 3). Several studies have focused on delusion as an early symptom of ND. In a cohort study of 487 patients it was reported at first clinical assessment in 9.9% of patients (11.8% in AD, 18.4% in bvFTD and lower percentages for progressive aphasia, cortico-basal syndromes and supranuclear palsy) [44]. In another study, among 372 patients with pathologically proven ND, 14.5% of the FTD-TDP and 10.2% of the DLB/AD groups had experienced delusion during the first 3 years of the disease, whereas it occurred only in 1.8% and 4.5% of the patients with AD and FTD-tau respectively [2].

Delusions in ND often exhibit thematic preferences, with common themes including persecution, reference, and jealousy, although variations may arise depending on the underlying etiology, as shown in Table 1 and Fig. 2 [2, 44].

OPEN IN VIEWER

Fig. 2

Overview of all psychotic symptoms in the main ND. AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; ND, neurodegenerative dementias.

Delusions are often accompanied by hallucinations usually of similar thematic content, with varying prevalence depending on ND subtypes [44]. For instance, in a cohort of patients with ND-related psychosis, 44.4% of the AD patients group with delusions also displayed hallucinations, 73.3% of the DLB/AD copathology group, and 76.9% and 41.7% of the FTD tau and FTD-TDP groups respectively [2].

Most patients with ND experience delusions as negative or threatening, with a varying degree of perceived harm reported in different ND subgroups as revealed by a neuropathological study in which delusions were reported harmful for 74% of the patients in the FTD-TDP group and half of the patients in the AD, DLB /AD and FTD-tau groups [2].

Misidentification delusions

Misidentification delusions, characterized by erroneous beliefs of duplication of self, others, or the environment (1), are observed in varying frequencies across different ND subtypes. The prevalence of misidentification ranges between 16.6% and 78.3% in DLB [28, 46], 15.8% and 34.2% in AD [28, 47], while it is rarely reported in FTD [28, 47], except for semantic variant Primary Progressive Aphasia (svPPA) (8.4% in a study including 24 patients with svPPA) [45]. Comparative studies indicate that DLB, AD, and FTD-TDP pathology are more likely to report misidentification than the other groups [2] and that misidentifications was strongly associated with DLB as compared to AD [39].

Various subtypes of misidentification delusions have been described, including misidentification of people, places, objects, reduplication of people or places, Capgras syndrome (a belief that a person has been replaced by an identical impostor), and phantom boarder syndrome (a belief that people (i.e., absent or deceased relatives, strangers ...) are in the house) are observed in more than 5% of patients with DLB [46, 47]. Two others subtypes are also described in the literature in patients with AD and DLB: the mirror sign in which the patient doesn’t recognize his or her reflection in the mirror, that is especially observed in patients with DLB and the TV sign in which the patient believes that characters appearing in television belong to reality [37].

Misidentification delusions, due to their high incidence, have been a subject of special focus in DLB. Among DLB patients, misidentification of people occurred in a frequency range of 13.8% to 33.3% [2, 47], misidentification of places (especially the patient’s home) was observed in 10.3% to 47.6% of cases [2, 47], and misidentification of objects occurred in 9.5% to 28% of cases [46, 47]. Additionally, phantom boarder syndrome was reported in a range of 2.9% to 31.4% [39–41, 46], while Capgras syndrome (CS) was found in 1.0% to 33.3% of cases [39–41, 46–48].

In AD, a similar trend was observed, albeit to a lesser extent, with a predominance of misidentification of places (2.7% to 28.1%) [2, 47], CS (9.4% to 15.9%) [38, 39], and phantom boarder syndrome (4.7% to 12.7%) [38, 39]. Data on the stage of the disease at which these symptoms occur are mostly lacking. However, a study reported a negative association between misidentification of home and the Mini Mental Status Examination score, reflecting global cognitive function in AD, suggesting that this symptom was more commonly observed in the advanced stages of the disease [49].

CS has garnered significant attention in the literature as a type of misidentification delusion primarily associated with ND. A study revealed that CS was attributed to underlying ND in 81% of a cohort of 47 patients, with DLB (26/47) and AD (7/41) being the main contributors [50]. Multiple studies have confirmed a higher occurrence of CS in DLB patients compared to those with AD (ranging from 1.0% to 33.3% and 9.4% to 15.9%, respectively) [38–41, 46–48]. In addition, CS did not emerge as a feature of FTD, except for cases reported in patients with svPPA [45]. Overall, CS appears to be the most common misidentification delusion, reported as the sole delusional symptom in 8.3% of DLB patients and 5.9% of AD patients [45]. Interestingly, a study suggested that CS might occur independently of cognitive status, at least in patients with DLB [48].

CS is most frequently directed towards the patient’s partner [51–54] or other relatives [55], but other targets have been reported, such as the patient themselves [56] or animals [57]. The characteristics of CS do not seem to differ whether it is caused by ND or PPD, as evidenced by a study involving 47 individuals where similarities in its description were observed across subjects with ND (n = 38) and those without (n = 2). However, concomitant visual hallucinations were more frequently reported in patients with CS related to ND [50].

Akin to CS, there have been reports of unusual delusions of duplication in DLB patients, such as a 77-year-old woman who referred to her professional caregiver as being two persons or a 83-year-old woman that believed her daughter had been duplicated with another caregiver [55, 58].

Paranoid delusions

Paranoid delusion is characterized by a fixed false belief that harm is being suffered or is imminent, and that the perpetrators are intentionally causing it [1]. In patients with ND-related psychosis, paranoid delusions are consistently reported as the most common type [36, 60]. The frequency of paranoid delusions varies across ND subtypes, ranging from 9.1% to 60.3% in AD [2, 39], 19% to 43.5% in DLB [2, 39], and 0% to 26.5% in FTD [2, 28].

Multiple subtypes of paranoid delusions can be observed in ND. The predominant scenarios reported for AD and DLB include theft (0% to 54.0% and 3.4% to 35.5% respectively), persecution (1.8% to 15.9% and 8.5% to 14.5%), jealousy or infidelity (0.9% to 19.0% and 1% to 7.2%), and abandonment (2.3% to 14.3% and 4.0% to 6.2%) [40, 61]. Although evidence is limited, theft was reported in 2.3% and 4.4% of patients with pathologically confirmed FTD in the tau and TDP groups respectively, persecution in 3.8% and 14.5%, and jealousy in 1.5% and 5.9% [2]. In another study, persecution was experienced by 11.34% of a clinical FTD cohort [16].

Persecution delusions appear as a common feature in reports of ND-related psychosis cases, not only in FTD [3, 18–21], DLB [58, 63], and AD [13, 64] but also in other neurodegenerative diseases such as Huntington’s disease [22, 24], Creutzfeldt Jakob disease [23], and Spinocerebellar ataxia type 2 [25]. These persecutory delusions are often accompanied with other themes, including jealousy or infidelity [22, 66], self-danger [12, 63], theft [12, 56], ruin [18, 23], inheritance of the house [22], and guilt [11]. Importantly, while most authors consider “paranoid” as an umbrella term including “persecution” as a subtype, an ambiguity in terminology exists in the literature that would benefit from harmonization to improve methodological uniformity in future studies.

Grandeur and erotomaniac delusions

Grandeur and erotomaniac delusions are characterized by grandiose ideas, which involve beliefs of possessing special powers, talents, knowledge, or abilities, and erotomania, which entails the illusion of being loved by another person [1]. In a cohort of pathology-confirmed ND, grandiose delusions were reported in 1.8% of the AD group, 8.5% in the DLB/AD copathology group, 3.8% in the FTD-tau group, and 14.5% in the FTD-TDP group, while erotomania was identified only in the FTD-TDP group (5.8%) [2]. Conversely, erotomania was not observed in any patient with AD or DLB in another cohort [59].

Cases of grandeur delusions have been documented in patients with FTD [5, 35], as well as erotomaniac delusions [67], which were reported several times in the form of confabulations about relationships with celebrities and children shared with them [65, 68]. Erotomaniac delusions were also reported in patients with DLB, presenting as the delusion that the general practitioner had fallen in love with the patient [62], and in AD [69].

Mystic delusions

Mystic delusions, characterized by delusions with religious content [1], have been mainly reported in patients with FTD, that may present with an increase in religious feelings and investment [18]. In some patients, these manifestations include instances of pure mystic delusions [3, 71] and confabulations regarding conversations with deceased relatives [65]. However, it is noteworthy that such delusions have not been consistently identified in larger cohort studies [59].

Somatic delusions

Somatic delusions, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), involve persistent false beliefs concerning the appearance or functioning of the body [1]. These delusions often revolve around the perception of an abnormality.

Overall, the frequency of somatic delusions in patients with ND appears to be relatively low. In AD, the estimated prevalence is around 11.2% [72], while in DLB [46] and FTD [16] cohorts, it is less than 5%. Among patients with psychosis, somatic delusions were reported in 6.1% of the DLB group, 2.9% of the AD group, and 5.3% in the VLOSP (Very Late-Onset Schizophrenia-Like Psychosis) group [59]. However, it is worth noting that somatic delusions have been particularly reported in a particular variant of FTD, known as the svPPA, where its frequency reaches 41.5% in the early stages [72].

Particular cases of somatic delusions have been documented in FTD [5, 7] and in AD, such as reduplication of the tongue [73] or as Koro syndrome, characterized by delusional anxiety caused by the fear of penile shrinkage [74]. Somatic delusions have also been reported in other neurodegenerative diseases[25]. Some authors have hypothesized that excessive somatic preoccupation in these cases might be due to an inability to identify and understand normal or minor body signals, a phenomenon termed “alexisomia” [5]

Other themes

In addition to the above-mentioned delusions, several other themes have been reported in the context of ND-related psychosis.

The partition delusion, where individuals believe that people or objects can pass through material borders, has been observed and reported in 6.1% of DLB cases and 14.3% of AD cases [59].

Delusion of pregnancy has been documented in four case reports of FTD patients [21, 76] and identified in one out of 100 patients with DLB [46].

Delusory parasitosis (also known as Ekbom syndrome) has been reported in four cases during the prodromal stages of DLB, often accompanied by multimodal hallucinations. These delusions manifested as feelings of ants in the head [77] or filaria infection of the nose and eyes [78]. In some cases, patients have even used insecticides in attempts to get rid of non-existent insects, leading to self-inflicted injuries [79]. A case of mixed parasitosis/persecutory delusion has also been described in a patient with FTD, who believed that persecutors had bugged his house [20].

Visual hallucinations

Visual hallucinations are the predominant hallucinatory modality in ND psychosis, with prevalence rates reported as follows: 50–69.6% in DLB [28, 41], 3.3–18% in AD [28, 39], and 0% –14.4% in FTD [16, 28]. Similarly, hallucinations are widely represented in neurodegenerative diseases among patients with psychosis [60], ranging between 81.8% and 93.9% in DLB [17, 59] and 54.3% in AD [59].

Early visual hallucinations are primarily observed in DLB, where they are observed at initial presentation in 18.75% of patients [39].

The content of visual hallucinations appears quite similar across ND. The most frequent manifestations are human figures in both DLB and AD, followed by animals [46, 59]. Numerous case reports in the literature confirm this predominance [56, 79] and highlight the congruence between hallucinations and delusional ideas, where abnormal perceptions tend to nurture delusions, such as parasitosis (26, 33), phantom boarder [67], or self-endangerment [10].

Auditory hallucinations

Auditory hallucinations are consistently reported as the second most frequent hallucinatory modality in ND. Similar to visual hallucinations, their prevalence is higher in DLB compared to other degenerative dementias, occurring in 8–35.5% of DLB patients [28, 46], while in AD, it is reported in only 1.2–4.6% of patients [28, 39] and in 0–3.1% of patients with FTD [16, 28]. Studies that focused on patients with ND-related psychosis found slightly higher prevalence of auditory hallucinations in DLB patients (22–40.8%) compared to AD patients (4–22.9%) [36, 59].

Notably, a vast majority of ND patients with auditory hallucinations also reported concomitant visual hallucinations [39].

In DLB and AD patients, auditory hallucinations primarily consisted of voices [39, 59] and were described as a background soundtrack accompanying visual hallucinations by 90% of a cohort of patients with DLB [41]. Importantly, the same study underlined that 71% of patients felt the auditory hallucinations as unpleasant [41].

On the other hand, musical hallucinations are an atypical pattern of auditory hallucinations in ND, with a low prevalence ranging from 0% in AD to 4.1% in DLB [59]. However, a study that described a cohort of patients with musical hallucinations found that 25% of the cases were caused by a neurological disorder, with ND, mostly DLB, accounting for two-thirds of the latter condition in this cohort [81]. Moreover, characteristics of musical hallucinations differed depending on the etiology, with musical hallucinations caused by ND more frequently involving religious songs and displaying a tendency to be more persistent over time [81].

Several case reports of auditory hallucinations in patients with ND, including FTD [5, 21], AD [13, 74], DLB [54, 77], and other neurodegenerative dementias [22, 25], have been published in the literature. Interestingly, a number of them reported an injunctive character of the hallucinations [20, 51]

Other hallucinatory modalities

Other hallucinatory modalities are rarely observed in ND, with prevalence rates of less than 3% in several cohort studies [28, 59]. However, a noticeable exception might be tactile hallucinations experienced by patients with parasitosis delusions [77–79].