Psychosis in Neurodegenerative Disease: Differential Patterns of Hallucination and Delusion Symptoms

Georges Naasan; Suzanne M. Shdo; Estrella Morenas Rodriguez; Salvatore Spina; Lea Grinberg; Lucia Lopez; Anna Karydas; William W. Seeley; Bruce L. Miller; Katherine P. Rankin

Disclosures

Brain. 2021;144(3):999-1012. 

In This Article

Results

A total of 372 patients met inclusion criteria, of which 111 patients had psychosis. The primary neurodegenerative diagnoses were: 111 Alzheimer's disease, 59 LBD/AD, 63 PSP, 44 CBD, 26 Pick's disease, 17 FTLD-TDP-A, 33 FTLD-TDP-B, and 19 FTLD-TDP-C. The demographic characteristics of patients across the major primary pathology diagnoses are presented in Table 1. There were no statistical differences in gender distribution or level of education across diagnostic groups, although patients with LBD/AD were more likely to be males. Patients with FTLD-TDP B were significantly younger at disease onset than patients with LBD/AD or PSP.

Frequency of Psychosis

Compared to the other diagnostic groups, patients with LBD/AD or with FTLD-TDP-A or -B were more likely to have psychosis consistently throughout their disease course rather than in isolated incidents (Table 1). Patients with FTLD-TDP-A and patients with LBD/AD were more likely to have hallucinations present in the first 3 years of the disease as compared to patients with Alzheimer's disease and patients with CBD (P < 0.0001) (Figure 1 and Table 1). The median number of distinct hallucination types co-occurring in a single patient was two for both patients with Alzheimer's disease and LBD/AD as compared to one type for patients with FTLD. The duration and frequency of hallucinations did not significantly differ across disease category. After removing patients with infrequent hallucinations (i.e. patients who experienced hallucinations once a year or less) and rerunning the analysis, none of these results changed meaningfully. Patients with LBD/AD, TDP-A and TDP-B were more likely to have delusions in the first 3 years of disease as compared to patients with Alzheimer's disease and CBD (P = 0.001) (Figures 1 and 2, Table 1 and Supplementary Table 1).

Figure 1.

Frequency of psychosis symptoms. Graph shows the frequency of psychosis symptoms across all major classes of neuropathology, including nature of psychosis (hallucinations or delusions) and whether the symptom appeared early (in the first 3 years after disease onset) or later in the disease course. AD = Alzheimer's disease.

Figure 2.

Psychosis subtypes by major pathology groups. Bars represent percentage of the patients in the sample with that class of primary pathology who exhibited the particular type of psychosis at some point during the course of their neurodegenerative disease. AD = Alzheimer's disease.

Non-formed Visual Hallucinations: Shapes, Shadows and Visual Misperceptions

Hallucinations described as shapes and colours occurred in 12.5% of patients with LBD/AD, significantly more than in patients with Alzheimer's disease (3.7%), FTLD-tau (1.5%) or FTLD-TDP (1.4%) (P = 0.002). In the two patients with FTLD-tau and non-formed hallucinations, one had Pick's disease with LBD pathology in the substantia nigra and the other had CBD with brainstem-only LBD pathology. Four patients with Alzheimer's disease (3.7%) had hallucinations of shapes and colours and none of them had LBD co-pathology, although one had a vascular infarct in the putamen.

Peripheral hallucinations described as 'shadows off the corner of the eye' occurred almost exclusively in patients with LBD/AD (17.5%) as compared to patients with Alzheimer's disease, FTLD-tau, and FTLD-TDP pathology (1.8%, 1.5%, and 1.4%, respectively; P < 0.0001). The only two patients with FTLD-tau who had peripheral hallucinations both had CBD and limbic TDP pathology. Moreover, two patients with Alzheimer's disease had hallucinations of peripheral shadows; one had LBD pathology confined to the amygdala and the other had limbic argyrophilic grain disease (AGD).

Visual misperceptions, wherein an existing visual stimulus appeared distorted or modified, also occurred significantly more frequently in patients with LBD/AD (19.6%) as compared to patients with Alzheimer's disease, FTLD-tau, and FTLD-TDP (3.7%, 3%, and 7.2%, respectively; P < 0.0001). One of the four patients with FTLD-tau and visual misperceptions had CBD pathology with LBD confined to the brainstem. In six patients with FTLD-TDP and visual misperceptions, one had brainstem only LBD, one had an infarct in the globus pallidus, and one had argyrophilic thorny astrocyte clusters (ATAC) in the amygdala consistent with ageing-related tau astrogliopathy (ARTAG) (Kovacs et al., 2016). In all groups, visual misperceptions were more likely to be new images as opposed to distortions of existing visual stimuli.

A logistic regression model (see 'Materials and methods' section) correctly classifying 96.4% of cases showed that patients with a Parkinson's disease Braak stage of 5–6 were 52 times more likely to have hallucinations of peripheral shadows than patients with no LBD pathology (P < 0.0001, Nagelkerke R2 = 34.4%). No other pathology significantly predicted this type of hallucination. Moreover, patients with Parkinson's disease Braak stage 5–6 were eight times more likely to have misperceptions than those with no LBD (P < 0.0001, R2 = 18.4%, correctly classifying 93.1% of cases).

Formed Visual Hallucinations: People, Animals, and Inanimate Objects

One-third of patients with LBD/AD had hallucinations of people significantly more frequently than patients with Alzheimer's disease (7.3%), FTLD-tau (6.8%), or any FTLD-TDP (6.1%, P < 0.0001). The majority of hallucinations of people were of strangers, while only 20% were of familiar people. Of the eight patients with Alzheimer's disease and hallucinations of people, one had an infarct in the putamen, and none had LBD co-pathology. Of the nine patients with FTLD-tau pathology who had people hallucinations, two had LBD confined to the brainstem, one had Alzheimer's disease Braak 6 and one had Alzheimer's disease Braak 2. Of four patients with FTLD-TDP, one had brainstem-predominant LBD and one had Alzheimer's disease Braak 6.

Hallucinations of animals occurred in 16.1% of patients with LBD/AD, more frequently than in patients with Alzheimer's disease (3.7%), FTLD-tau (4.1%), or FTLD-TDP (8.7%), though the differences were not statistically significant. The one patient with FTLD-TDP-C who had hallucinations of animals was the only patient with TDP-C in the entire cohort to have any hallucinations and had concomitant focal traumatic tauopathy in frontal, temporal and limbic structures. Of the three patients with FTLD-TDP-B who had animal hallucinations had LBD Braak 3, and one of two patients with FTLD-TDP-A who had animal hallucinations had ATAC confined to the amygdala. Of six patients with FTLD-tau, one had LBD Braak 4 co-pathology and another had limbic AGD.

Hallucination of insects was seen only in patients with LBD/AD (7.3%), Alzheimer's disease (5.6%), PSP (1.6%) and FTLD-TDP-B (3%) with no statistically significant difference in prevalence across groups. Nevertheless, the one patient with TDP-B who had insect hallucinations had a vascular infarct in the globus pallidus and limbic AGD, whereas the one patient with PSP who had insect hallucinations had concomitant Alzheimer's disease Braak 4.

Ten per cent of patients with LBD/AD hallucinated inanimate objects as compared to none from the FTLD-tau and FTLD-TDP groups, and only 2.8% of patients with Alzheimer's disease (P < 0.0001).

A logistic regression model correctly classifying 92.8% of cases showed that patients with a Parkinson's disease Braak stage 5–6 were seven times more likely to have hallucinations of animals than patients with no LBD pathology (P = 0.01, R2 = 14.3%). Moreover, patients with a Parkinson's disease Braak stage 5–6 were 11 times more likely to have hallucinations of people than those with no LBD (P < 0.0001, R2 = 23.8%, classifying 89.2% of cases). Finally, patients with Parkinson's disease Braak Stage 5–6 were seven times more likely to have hallucination of objects than those with no LBD pathology (P = 0.021, R2 = 34.5%, classifying 97.3% of cases).

Non-visual Hallucinations: Auditory, Tactile and Olfactory

Auditory hallucinations were reported in 4.3% of all patients and across all four main pathology categories without statistical differences across groups (Table 2). Only one patient with LBD/AD and one patient with Pick's had olfactory hallucinations. Only two patients with LBD/AD and one patient with TDP-B had tactile hallucinations. None of the patients in our cohort reported gustatory hallucinations.

Hallucinations: Other Characteristics

Hallucinations were reported to move in 14.3% of patients with LBD/AD as compared to only 2.8% of patients Alzheimer's disease and 1.5% of patients with FTLD-tau, while none of the patients with TDP reported moving hallucinations (P < 0.0001). Moreover, both patients with FTLD-tau and moving hallucinations had brainstem-predominant LBD co-pathology. A logistic regression model showed that patients with a Parkinson's disease Braak staging of 5–6 were 11 times more likely to have hallucinations that moved than patients with no LBD pathology (P = 0.001, R2 = 27.8%, classifying 96.1% of cases).

In a subgroup analysis of all patients with hallucinations (n = 79), there was a trend for patients with LBD/AD to have insight during and after their hallucinatory episode as compared to patients with FTLD-tau or FTLD-TDP (P = 0.026 and 0.044, respectively, threshold for significance set at P = 0.02041 per B-Y method for k = 6; Table 3). None of the patients with Pick's (n = 1), CBD (n = 3), or TDP-B (n = 8) who had hallucinations had insight, either during the episode or in retrospect. Hallucinations were reported to occur in association with sleep (waking up from sleep or falling asleep) in 61.5% of patients with Alzheimer's disease who hallucinated, significantly more frequently than in all other patients (P = 0.002). Hallucinations were reported around sleep in a quarter of patients with LBD, but this was not statistically different from other groups. There was a non-significant trend in which patients with LBD were more likely to interact with their hallucinations as compared to patients with Alzheimer's disease, FTLD-tau, or FTLD-TDP (32.1% versus 15.4%, 0%, and 13.3%, respectively, P = 0.033). Of the two patients with TDP who interacted with their hallucinations, both had TDP-B and one had concomitant LBD Braak 1. Of the two patients with Alzheimer's disease who interacted with their hallucinations, one had LBD only in the amygdala. Hallucinations were reported as 'disturbing' in equal proportions across diagnostic groups, ranging from 11% to 17% of patients.

The Feeling of Presence

The feeling of presence, defined as a reported feeling of someone present in the room when no one is actually there, occurred in 15.5% of patients with LBD/AD, significantly more than in patients with any other pathology (0.9% in Alzheimer's disease, 1.5% in FTLD-tau, and 1.5% in FTLD-TDP, P < 0.0001). Of the four patients who reported the feeling of presence and did not have primary LBD/AD, one had LBD Braak 3 co-pathology. A logistic regression model showed that patients with a Parkinson's disease Braak staging of 5–6 were 16 times more likely to have the feeling of presence than patients with no LBD pathology (P < 0.0001, R2 = 26.2%, classifying 96.2% of cases).

Bizarre and Non-bizarre Delusions

Non-bizarre delusions were the most common type of delusions across all diagnoses and occurred at a frequency of 17.3% in the entire cohort. They occurred in a third of patients with TDP pathology and in 22% of patients LBD/AD pathology, significantly more frequently than in other diagnostic groups (P < 0.0001; Table 2 and Table 4). Conversely, bizarre delusions were not common and were found in only 3.8% of all patients. They appeared to occur more frequently in patients with any FTLD-TDP and in patients with LBD/AD. As an example of a bizarre delusion, a patient with a pathological diagnosis of PSP and Alzheimer's disease Braak 4 believed that his arm and other body parts were replaced by robotic implants. This was the only patient in our cohort who had a delusion of misidentification of body parts. A patient with FTLD-TDP-A and AGD was convinced that his wife had been replaced by a demon. Ideas of reference only occurred in four patients who had a pathology of Alzheimer's disease, LBD/AD or TDP-B.

Paranoia, Persecutory Delusions and Delusions of Jealousy

Paranoid non-bizarre delusions were the most common subtype of delusions and occurred significantly more frequently in patients with any FTLD-TDP (26.5%) as compared to patients with Alzheimer's disease (9.1%) and FTLD-tau (8.3%). In particular, paranoid delusions were most frequent in patients with TDP-A (29.4%), TDP-B (28.1%), and LBD/AD (19%).

Within the category of paranoid delusions, persecutory delusions encompassing delusions of theft, hurt, and intrusion to the patient's own home occurred more frequently in patients with FTLD-TDP-A–C (11.8, 15.2 and 15.8%, respectively) as compared to patients with Alzheimer's disease (1.8%). In particular, delusions of intrusion to home drove these findings (12.5% in TDP-B versus 0.9% in Alzheimer's disease). Delusions of jealousy were reported in only a small number of patients distributed evenly across most neuropathological diagnoses. Logistic regression modelling did not significantly discriminate any of these diagnostic groups.

Delusions Regarding a Place

Delusions regarding a place (e.g. 'home') were significantly more frequent in patients with LBD/AD pathology (10.3%) than in any other group, and did not appear at all in patients with FTLD-TDP. As an example, one patient with LBD/AD reported that when he was not paying attention, someone was moving his house to a different location. He found it odd that the interior of the house remained the same despite the fact that the house had moved many miles away. None of the patients with CBD or Pick's disease had delusions regarding a place. A logistic regression model showed that patients with a Parkinson's disease Braak staging of 5–6 were five times more likely to have delusions regarding a place than patients with no LBD pathology (P = 0.017, R2 = 27%, classifying 96.4% of cases).

Delusions of Misidentification of People

Delusions of misidentification of people were significantly more frequent in patients with LBD/AD (13.8%) and patients with FTLD-TDP (7.2%) when compared to patients with other diagnoses. None of the patients with FTLD-TDP who had this delusion had an LBD co-pathology, except for one who had LBD at a very early Parkinson's disease Braak 1 stage. A logistic regression model showed that patients with a Parkinson's disease Braak staging of 5–6 were 10 times more likely to misidentify people than patients with no LBD pathology (P = 0.001, R2 = 34.9%, classifying 95% of cases) and that patients with FTLD-TDP pathology were also 10 times more likely to misidentify people than patients with no FTLD-TDP pathology (P = 0.011).

Only one patient in our cohort had a true Capgras delusion, and believed that his physician was an imposter. This patient had a diagnosis of FTLD-TDP-B along with MND pathology, no contributing Alzheimer's disease or LBD pathology, and an expansion in the C9orf72 gene.

Delusions of Grandeur and Erotomania

Grandiose delusions were primarily seen in patients with FTLD-TDP-B pathology at a frequency of 9.4% (supplementary Table 1) and with a non-significant trend to be more frequent than in patients with Alzheimer's disease, LBD/AD or FTLD-tau-Pick's pathology (P = 0.022). Delusions of erotomania were only reported in patients with TDP pathologies, suggesting that this delusion subtype is most predictive of TDP pathology. Even though these two delusions are classified separately in the DSM-V, and because (i) they have comparable neurological mechanism involving inflation of self perception; and (ii) they seem to occur in a similar pattern across diagnoses, we combined them together under one category of self-elevating delusions and performed a logistic regression model, which showed that patients with FTLD-TDP were 22 times more likely to have self-elevating delusions than patients with no FTLD-TDP pathology (P = 0.009, R2 = 31.1%, classifying 97.6% of cases).

Direct Comparison of the FTLD Pathologies

For clarity, a direct comparison of the psychosis profile of the two main FTLD molecular classes is summarized in Table 5. Whereas none of the hallucination subtypes differentiated between FTLD pathologies, the presence of delusions in general, as well as delusions that are bizarre, paranoid, persecutory, intrusionary, erotomanic, or grandiose, and delusions of misidentification, all were significantly more likely to be present in FTLD-TDP than in FTLD-tau.

Genetic Analysis

Genetic analysis is summarized in Table 1 and Table 6. There was an equal proportion of APOE ε4 carriers with and without psychosis across all diagnoses, except in patients with Pick's disease, in whom 2/4 with psychosis had an APOE ε4 allele versus 4/22 without psychosis. In patients with FTLD-TDP-A, there was a trend towards a higher proportion of C9orf72 expansions in patients with delusions (n = 2 mutation positive/5 mutation negative) compared to those without (n = 1/10), but there was equal proportion of GRN mutations in both groups. Thirty-three patients with FTLD-TDP-B received genetic testing and 12 (36.4%) had an expansion in the C9orf72, in equal proportion between patients with and without delusions (Table 6).

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