Psychosis in Neurodegenerative Dementias: A Systematic Comparative Review

Abstract

Background:

Psychosis, characterized by delusions and/or hallucinations, is frequently observed during the progression of Alzheimer’s disease (AD) and other neurodegenerative dementias (ND) (i.e., dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD)) and cause diagnostic and management difficulties.

Objective:

This review aims at presenting a concise and up-to-date overview of psychotic symptoms that occur in patients with ND with a comparative approach.

Methods:

A systematic review was conducted following the PRISMA guidelines. 98 original studies investigating psychosis phenotypes in neurodegenerative dementias were identified (40 cohort studies, 57 case reports).

Results:

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. Throughout all stages of these diseases, noticeable patterns emerge depending on their underlying causes. Misidentification delusions (16.6–78.3%) and visual hallucinations (50–69.6%) are frequently observed in DLB, while paranoid ideas and somatic preoccupations seem to be particularly common in AD and FTD, (respectively 9.1–60.3% and 3.10–41.5%). Limited data were found regarding psychosis in the early stages of these disorders.

Conclusions:

Literature data suggest that different ND are associated with noticeable variations in psychotic phenotypes, reflecting disease-specific tendencies. Further studies focusing on the early stages of these disorders are necessary to enhance our understanding of early psychotic manifestations associated with ND and help in differential diagnosis issues.

Keywords

Alzheimer’s disease delusion dementia dementia with Lewy bodies frontotemporal degeneration hallucinations neurodegenerative disease psychosis

INTRODUCTION

Psychosis, a neuropsychiatric condition characterized by delusions and/or hallucinations, often with limited insight, can arise within both psychiatric and neurological contexts [1]. Among the diverse spectrum of neurological disorders, neurodegenerative dementias (ND) stand out as significant contributors to the manifestation of psychosis, with conditions such as Alzheimer’s disease (AD), frontotemporal degeneration (FTD), and dementia with Lewy bodies (DLB) not unfrequently associated with its presence [2].

In the diagnostic landscape, differentiating ND-related psychosis from late-onset psychiatric disorders sometimes poses an important challenge, especially during early stages of the disease, when cognitive impairments and anatomical-biological abnormalities may not be readily apparent [3 –15]. Misclassifications are not uncommon, with some individuals initially diagnosed with primary psychiatric disorders (PPD), which refer to mental health conditions primarily rooted in psychiatric factors, rather than organic and/or neurological causes. For instance, in a cohort of 97 patients with FTD, 73 received an inadequate diagnosis at baseline that was a PPD for half of them [16]. Similarly, in a sample of 34 patients without dementia diagnosed with very-late onset schizophrenia-like psychosis (VLOSLP), 32.4% displayed markers indicative of DLB on diagnostic workup [17]. Numerous case reports of patients with DLB [11], AD [12 –14], FTD [3 , 18–21], or other neurodegenerative processes [22 –25] illustrate this issue. Conversely, late-onset schizophrenia can also be misdiagnosed as neurodegenerative disorders, further complicating the diagnostic process [4].

Another key issue lies in accurately identifying the underlying etiology in ND patients with psychosis. Patients with AD, for instance, may be misdiagnosed as having DLB due to the presence of psychotic symptoms [26]. Similarly, in a neuropathological study patients clinically misdiagnosed as having FTD that were eventually found to display AD pathology, were more likely to have displayed delusions and hallucinations during the course of their disease, indicating the possible influence of psychotic symptoms on clinical diagnosis [27]. The impact of this misdiagnosis on patient care cannot be understated, as it may lead to diagnostic delays, inappropriate medication usage with avoidable side effects, and missed opportunities for genetic counseling [3 , 22].

Despite the growing body of evidence on psychosis in ND, there remains a scarcity of direct comparisons of psychotic symptoms across different neurocognitive disorders [2, 28]. Furthermore, studies specifically focusing on psychosis as an early and/or prominent feature of the disease are limited. Therefore, the objective of this study is to fill this critical knowledge gap by providing a concise and comprehensive summary of the existing evidence concerning psychotic symptoms in the three main neurocognitive diseases (AD, DLB, and FTD) through a comparative approach, with a particular interest for early stages symptoms.

Through a systematic review of the latest research, our aim is to assist clinicians in making accurate differential diagnoses and to identify potential avenues for further investigation. By shedding light on the intricacies of psychosis in ND, we hope to advance our understanding and enhance patient care for those affected by these complex neurological conditions.

METHODS

The present systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive bibliographic search was conducted in the PubMed database during February 2023, utilizing a combination of specific keywords (Supplementary Table 5). The search terms encompassed “neurodegenerative disease,” “frontotemporal dementia,” “dementia with Lewy bodies,” and “Alzheimer’s disease,” along with psychiatric terms such as “psychosis,” “primary psychiatric disorders,” “delusions,” and “dementia-related psychosis.” Of note, Parkinson’s dementia did not fall within the scope of our research, given the late onset of psychotic symptoms which do not interfere with the diagnostic process.

The inclusion criteria were established to select studies relevant to the scope of the review. The selected articles needed to fulfill the following criteria: 1) Present original data in the form of retrospective or prospective cohort studies or case reports; 2) Have a publication date later than the first international diagnostic criteria publication date, i.e., after 1998 for behavioral variant of FTD, 1996 for DLB, and 2011 for the first criteria for AD, including the use of biomarkers; 3) Focus on clinical features, diagnosis, and differential diagnosis strategies, excluding studies centered on pathophysiology, genetics, epidemiology, prevention, management, prognosis, caregivers, and economics; 4) Be written in either French or English.

Articles were initially screened based on their title and abstract, followed by a thorough examination of the full texts. Articles that did not meet the predetermined inclusion criteria were excluded from the review.

All articles meeting the inclusion criteria were included in the review, irrespective of the disease stage within the cohort population. In cases where early-stage patient subgroups were included, their outcomes were specifically highlighted. Papers included in the review were read in full text and all data regarding psychotic symptoms were extracted in the review without use of a pre-established reading grid.

The process of article selection, reading, and data extraction was performed by both the first and last authors to ensure meticulousness and consistency throughout the review. Final decision was taken after consensus discussion in case of disagreement.

RESULTS

The results from the comprehensive search are summarized in Fig. 1 and Supplementary Table 1. A total of 97 studies, comprising 40 cohort, case-control and case series studies and 57 case reports, were included in this review.

Fig. 1

Flow chart of the study.

Considering the substantial heterogeneity observed among the study results, stemming from variable methodologies, a meta-analysis could not be conducted. These disparities primarily stemmed from the use of different diagnostic criteria across the cohort studies, the most employed being McKhann et al.'s 1984 criteria [29] for AD (used for 42.31% of the cohorts included only), McKeith et al.'s 2005 criteria [30] for DLB (used for 30% of the cohorts included only), and Rascovsky et al.'s 2011 criteria [31] for bvFTD (used for 26.32% of the cohorts included only). Furthermore, variations in the assessment tools for psychosis added to the methodological diversity, with the Neuropsychiatric Inventory (NPI) being the most frequently used tool, adopted in only 43.59% of the studies. (Supplementary Table 6). In this context, we have therefore chosen to present prevalence ranges (minimum and maximum among published studies) rather than to calculate a mean estimate at high risk of bias.

The present work is a critical and synthetic analysis of the findings reported in all the selected studies. While we included case reports to enrich our understanding of the symptomatology, they were not incorporated into any quantitative analyses.

ND-related psychosis: demographic overview

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].

Delusions

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].

Table 1

Prevalence of delusions subtypes described in cohorts of patients with ND

	AD	DLB	FTD
Any delusion	5.82–51.2%	32.8–60.9%	10.5–34.8%
Misidentification delusions
All-misidentifications	15.8–34.2%	16.6–78.3%	0–8.3%
⇒ Misidentification of people	3.4–4.5%	13.8–33.3%	0–7.2%
⇒ Misidentification of places/of the house	2.7–28.1%	10.3–47.6%	0–2.3%
⇒ Misidentification of objects	4.1%	9.5–28%	0%
⇒ Phantom-border disorder	4.7–12.7%	2.9–31.4%	0%
⇒ Reduplication of people	No data	10%	No data
⇒ Reduplication of places	9.5%	6%	0%
⇒ Reduplicative paramnesias	7.5%	23,8%	0%
⇒ Capgras syndrome	9.4–15.9%	1.0–33.3%	0%
⇒ Belief that absents relatives are in the house	No data	6%	No data
⇒ Belief that deceased relatives are still alive	No data	5%	No data
⇒ TV sign	1.39–6.3%	2.9–19.0%	0%
⇒ Mirror sign	1.2–4.8%	0–9.83%	0%
Paranoid ideas
All-paranoid ideas	9.1–60.3%	19–43.5%	0–26.5%
⇒ Persecution	1.8–15.9%	8.5–14.5%	3.8–14.5%
⇒ Theft	0–54.0%	3.4–35.5%	2.3–4.4%
⇒ Jealousy or infidelity	0.9–19.0%	1–7.2%	1.5–5.9%
⇒ Abandonment	2.3–14.3%	4.0–6.2%	No data
⇒ Self-danger	No data	21.3%	No data
Self-elevating delusions
⇒ Erotomania	0–1.6%	0%	0–5.8%
⇒ Grandeur	1.6–1.8%	8.5%	3.8–14.5%
Mystic delusions
All-mystic delusions	No data	No data	No data
Somatic delusions
All-somatic delusions	0–11.2%	3–5.0%	3.10–41.5%
⇒ Pregnancy delusion	No data	1%	No data
⇒ Cotard syndrome	0.7%	0%	0%
Other characteristics among patients with psychosis
Multiple	58.6%	No data	No data
Harmful	50%	50%	74–58%
Hallucinations associated	44.4%	73.3%	41.7–76.9%

ND, neurodegenerative dementias; AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; Results are presented from cohorts of patients diagnosed clinically or neuropathologically with neurodegenerative diseases, reporting the prevalence of delusions over the entire disease course, excluding cohorts of psychotic patients due to incomparability. with non-selected dementia cohorts.

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].

Hallucinations

Hallucination is defined as a sensory perception in the absence of a corresponding stimulus, described according to the sensory domain in which it occurs [1].

Among the various studies, the highest prevalence of hallucinations was observed in DLB, ranging from 29.2% to 78% [2 , 46], surpassing FTD (6.9% –50%) [2 , 43] and AD (4.5% –26.1%) [2 , 80] (Supplementary Table 4). Notably, in FTD, a marked heterogeneity in the frequency of hallucinations has been reported, depending on the underlying pathology, with the highest prevalence observed in patients with TDP-43 pathology, particularly in those with C9Orf72 mutations [2].

Examining hallucinations at the early stages of ND, a study reported a prevalence of 4.5% in a cohort of 1,227 patients recently diagnosed with probable AD, a number that did not significantly differ from that in nondemented individuals over 65 years old [80]. Another study highlighted that psychosis (i.e., hallucinations and/or delusions) occurred during the first 3 years of the disease in half of the patients with FTD-TDP pathology and LBD/AD copathology [2].

The content and modalities of hallucinations may vary depending on dementia etiology as shown in Table 2 and Fig. 2 [2]. However, visual hallucinations are the most common modality in ND, followed by auditory hallucinations, while other modalities are infrequent [16 , 80]. Multimodal hallucinations, occurring in multiple sensory modalities, are not uncommon, especially in DLB (40.8%), and to a lesser extent in AD (25.7%) [41].

Table 2

Prevalence of hallucinations subtypes described in cohorts of patients with ND

	AD	DLB	FTD
Any hallucinations	4.5–26.1%	29.2–78%	6.9–50%
Minor phenomena
⇒ Illusions	0%	12.5%	No data
⇒ Feeling of presence	0.9%	15.5–23%	1.5%
Complex visual hallucinations
All-visual hallucinations	3.3–18%	50–69.6%	0–14.4%
⇒ Humans	45.7%	65–71.4%
⇒ Animals/insects	11.4%	16.3–29%
⇒ Objects		18%
Auditive hallucinations
All-auditive hallucinations	1.2–4.6%	8–35.5%	0–3.10%
⇒ Voices	11.4–35.3%	16.3–35.3%
⇒ Music	0%	4.1%
⇒ Noises/Sound	14.3%	6.1%
⇒ Association with visual hallucination		80–90.9%
Tactile hallucinations
All-tactile hallucinations	0%	0–3.7%	0–2.06%
Olfactive hallucinations
All-olfactive hallucinations	0%	0–3.7%	0–1.03%
Gustative hallucinations
All-gustative hallucinations	0%	0%	0–1.03%
Other characteristics
Multimodal	25.7%	40.8%
Harmful/Disturbing	16.7%	11.1–71%	13.3–15.8%
Delusions associated	42–53.3%	53.6%	52.4–66.7%

ND, neurodegenerative dementias; AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; Results are presented from cohorts of patients diagnosed clinically or neuropathologically with neurodegenerative diseases, reporting the prevalence of hallucinations over the entire disease course, excluding cohorts of psychotic patients due to incomparability.

As previously emphasized, the co-occurrence of hallucinations and delusions is observed in 42% –53.3% of patients with ND-related psychosis [2, 80].

Finally, the emotional experience associated with hallucinations in patients with ND has been described to be more often negative in AD than in DLB [60].

Minor phenomena

“Minor phenomena” is a term that encompasses various disturbances of perception and experience, such as illusions, palinopsia, pareidolia, synesthesia, feeling of passage, and feeling of presence. These phenomena are not complex enough to be classified as visual hallucinations [1].

Illusions, which refer to misperceptions of sensory stimuli [1], are more commonly observed in neurodegenerative diseases than in psychiatric disorders [60]. Among ND, they are considered highly suggestive of DLB, as evidenced by a study reporting a prevalence of 12.5% in the DLB group, while no patients with AD reported this symptom [39].

On the contrary, the feeling of presence, denoting the impression of a person’s presence nearby, is seen as a core symptom of DLB psychosis, experienced by 15.5% –23% of DLB patients [2, 46]. However, a recent comparative study found that it might be more frequent in patients with psychosis related to PPD (39.3%) than to ND (19.1%) [60]. It should be noted that feeling of presence, whose mechanism is usually considered akin to hallucinations, is not necessarily associated with phantom boarder syndrome, whose mechanism rather appears delusional.

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].

Insight

Data regarding insight, i.e., the ability to identify the pathological nature of the psychotic symptoms in patients with ND-related psychosis, are limited. While resistance to contradictory evidence is part of delusion’s definition, some patients may have incomplete adherence to their false belief and/or partial ability to criticize them. Indeed, a study reported partial or complete preservation of insight in both patients with AD pathology and LBD/AD co-pathology during hallucinations (40% and 52.6%, respectively) and retrospectively (40% and 61.1%), as compared to patients with FTD-tau and FTD-TDP (14.3% and 8.3% during the hallucination, 8.3% and 16.7% after) [2].

Interestingly, another study provided contrasting complementary results by showing that patients with ND-related psychosis had more insight than patients with primary psychiatric psychosis experiencing visual hallucinations. However, there was no significant difference in insight between the two groups of patients with auditory hallucinations [60].

DISCUSSION

Psychosis is frequent in the progression of neurodegenerative diseases and is occasionally observed in the initial stages, making it challenging to differentiate patients with ND-related psychosis from patients with psychiatric disorders. Considering the limited data available on psychosis in early ND, we have presented the findings from all available studies that explored psychosis phenotypes throughout the progression of the main neurodegenerative diseases, that are summarized in an easily readable way in Fig. 2. Notably, certain patterns emerged within the groups, such as misidentification delusions and visual hallucinations in DLB, paranoid ideas in AD, and somatic preoccupations in FTD.

However, data varied significantly among the studies, partially due to differing methodologies. The diversity in criteria used to define psychosis, the selection of populations based on various diagnostic criteria, and the use of different tools to assess the multiple aspects of delusions and hallucinations led to disparate results. To address this measurement bias, one strategy is to validate and ensure the comparability of these tools. For instance, a study that compared the prevalence of delusional misidentification in a sample of 195 subjects with ND using two different scales, NPI and MDQ, found similar prevalence rates of 33.3% and 36.0%, respectively [47]. Additionally, working with neuropathological samples ensuring definite diagnoses can help eliminate selection bias related to differing diagnostic criteria [2]. Hence, there is a genuine need for methodological uniformity in future studies on this subject. Moreover, while our systematic review aimed at capturing the prevalence of the various psychotic symptoms observed in ND, the infrequent documentation of certain subtypes of delusions in the literature may have limited the validity of reported prevalences. Additionally, it would have been interesting to compare prevalence of psychotic symptoms in ND to the one reported in healthy elderly subjects. However, our research retrieved only one study that included a group of 313 individuals aged 60 and older without cognitive deficits or overt psychotic disease. In this study 20% of those people reported one or more psychotic phenomena during the past month that were mainly minor phenomena (13%) and hallucinations (9%). Importantly, no individual reported verbal auditory hallucinations or delusions in this study [82].

In addition to precise characterization of symptoms, improvement of diagnosis accuracy in patients with ND-related psychosis implies delineation of at-risk populations and identification of contributing factors. First, the incidence of psychosis as the initial behavioral symptom in AD is correlated with age at onset, with a higher prevalence (7%) observed after the age of 79 compared to before 60 years (3%) in a cohort study of 7,815 patients (3%) [34]. In line with this, a younger age at onset was reported to be associated with an increased risk of misdiagnosis of PPD in patients with FTD-related psychosis [16]. Family psychiatric history was also 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 seem to play a significant role in the occurrence of psychosis in FTD patients, with a notable association observed with the C9Orf72 mutation [3 , 35]. A study, involving a cohort of 79 patients, investigated the neural correlates underlying psychotic symptoms in frontotemporal dementia associated with the C9orf72 gene expansion [83]. Carriers of the C9orf72 expansion displayed a higher likelihood of experiencing psychotic symptoms, including delusions and hallucinations, compared to non-carriers (64% vs. 26%), and these symptoms were more severe. Although the specific mechanisms remain poorly understood, the study revealed an association between psychotic symptoms in C9orf72 expansion carriers and atrophy in a cortical and subcortical network, similar to the one observed in other psychotic disorders such as schizophrenia [83].

Very few studies have focused on psychosis at the time of onset, despite it being a critical period for accurate diagnosis, with a high risk of misclassification as either an inappropriate ND or a primary psychiatric disorder. While clinical scales have been designed to distinguish between FTD and PPD [84] no such tools exist for the distinction between various ND presenting with early and/or prominent psychotic features. In this context, biomarkers have progressively gained importance. In addition to cerebrospinal fluid AD biomarkers assessment, measurement of neurofilaments levels that reflect neuroaxonal damage in either cerebrospinal fluid and/or plasma has been reported as a promising marker. However, while numerous studies have demonstrated that neurofilaments might be used to distinguish between FTD and PPD [85], a recent study showed disappointing properties for the discrimination between different ND in a large clinical practice cohort [86]. Genetic testing, particularly for the C9Orf72 mutation, is another useful option as FTD patients carrying a C9Orf72 mutation have been consistently found to be more likely to present with psychosis [87 –89]. Altogether, these tools may help with differential diagnosis, but most of them being FTD-focused, there is major gap remaining regarding differential diagnosis between ND in general. To address this gap, we advocate for the development of new multimodal diagnostic and/or tools that would help clinicians identifying the ND underlying late-onset psychosis and adapting investigations accordingly. A detailed and comparative knowledge of psychosis phenotypes across the different diseases appeared as a mandatory prerequisite to reach this goal. Our results might thus serve as a foundation for future studies targeting the assessment of psychosis associated with ND.

Early diagnosis of dementia in the presence of isolated psychotic symptoms is key for personalized early intervention. While the impact of early treatment of psychosis on the progression of ND is not clear, judicious use of antipsychotics with frequent reassessment improves efficacy and tolerance [90].

In conclusion, the literature suggests notable trends in the phenotypes of psychosis associated with different ND. Development of diagnostic tools for ND-associated late-onset-psychosis is needed to allow more accurate and timely diagnoses.

AUTHOR CONTRIBUTIONS

Coralie Cressot (Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Visualization; Writing – original draft; Writing – review & editing); Agathe Vrillon (Writing – review & editing); Matthieu Lilamand (Writing – review & editing); Hélène Francisque (Writing – review & editing); Aurélie Méauzoone (Writing – review & editing); Claire Hourregue (Data curation; Writing – review & editing); Julien Dumurgier (Data curation; Writing – review & editing); Emeline Marlinge (Writing – review & editing); Claire Paquet (Data curation; Writing – review & editing); Emmanuel Cognat (Conceptualization; Methodology; Project administration; Resources; Supervision; Writing – original draft; Writing – review & editing).

Footnotes

ACKNOWLEDGMENTS

The authors express their gratitude to the Journées de Neurologie de Langue Française association for generously providing financial support for Dr. Cressot’s research.

FUNDING

Dr. Cressot received a master’s grant from Journées de Neurologie de Langue Française.

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

DATA AVAILABILITY

The data supporting the findings of this study are available within the article and/or its supplementary material.

The supplementary material is available in the electronic version of this article: .

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