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


Brain. 2021;144(3):999-1012. 

In This Article

Materials and Methods


We screened 830 patients that came to autopsy at the University of California San Francisco Memory and Aging Center between 1999 and 2017 who had autopsy-confirmed primary neurodegenerative disease. Full pathology reports of all participants were reviewed. Patients were screened into the psychosis group if delusions or hallucinations were reported on the Neuropsychiatric Inventory (NPI) (Cummings et al., 1994) or the Alzheimer's Disease Research Center (ADRC) UDS Symptom Checklist at any time during their illness. The medical records of this subgroup were reviewed, and participants were excluded if details regarding their psychosis were absent or if their pathology reports were incomplete. Patients with no reported psychosis on the NPI or the ADRC symptom checklist were included in the control group if they had available pathology reports. If pathology reports mentioned psychosis as part of the clinical syndrome for patients who were originally assigned to the control group, their full medical charts were reviewed and they were switched to the case group if psychosis was verified. All patients or their surrogates consented to participate in the study, and the protocol was approved through the institution's internal review board, in accordance with the Declaration of Helsinki.

Chart Review

Medical records were systematically reviewed for information about patients' psychosis by trained coders who were blind to neuropathological diagnosis. To maximize reliability among coders, 20% of the charts of patients with psychosis were rated by two coders and discrepancies were discussed, resolved, and incorporated into an enhanced coding manual. Hallucinations were classified by sensory modality (visual, auditory, tactile, and olfactory) and by content of the hallucinated stimulus (visual misperceptions, simple visual hallucinations of shapes and colours, well-formed visual hallucinations including of people or animals, and non-visual hallucinations). Other characteristics of visual hallucinations, such as peripheral/extracampine hallucinations (Wood et al., 2015) and hallucinations of images that move were also coded separately. Delusion subtypes were selected according to the DSM-5 criteria. First, all delusions were subclassified into either bizarre or non-bizarre based on the definition that non-bizarre delusions are conceivably possible whereas bizarre fall outside of the realm of possibility. Then, delusions were divided into five major groups including: (i) erotomanic; (ii) grandiose; (iii) jealous; (iv) persecutory; and (v) somatic (American Psychiatric Association, 2013). In addition, we added a category to capture delusions of misidentification of people, including the Capgras delusion, and for delusions regarding a particular place, including a person's own home and reduplicative paramnesia. We further subclassified persecutory delusions into delusions of theft, intention to hurt, intrusion into home, and suspiciousness, for paranoid delusions that did not meet any of the other classifications. Finally, we included the feeling of presence, an overwhelming feeling that another person is present in the same room when no one is there, as its own category as its classification is unclear (Nagahama et al., 2007). Operational definitions for all psychosis classifications are presented in the Supplementary material. The duration and frequency of psychosis were also recorded.

Neuropathological Assessment

The neuropathological procedure is detailed in the Supplementary material. We classified patients into major categories according to four primary pathologies: (i) Alzheimer's disease without Lewy body disease (LBD) defined as a primary pathology of Alzheimer's disease meeting the ADNC criteria (Montine et al., 2012) without concomitant LBD or with LBD showing a Parkinson's disease Braak stage < 3; (ii) mixed LBD and Alzheimer's disease (LBD/AD), defined as concomitant Alzheimer's disease and LBD pathology where the Parkinson's disease Braak stage was ≥ 3; (iii) frontotemporal lobar degeneration with TDP inclusions (FTLD-TDP), including types A–C; and (iv) FTLD-tau, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease. Patients with FTLD were diagnosed according to international consensus criteria (Mackenzie et al., 2011). All patients with other primary pathologies were excluded from the analysis to constrain scope and to avoid creating many small subgroups with limited statistical power. In addition to classifying patients according to primary pathological diagnoses, we also coded all contributing pathologies as either present/absent. For example, if a patient had a primary pathology of FTLD-TDP-B, along with MND pathology, Alzheimer's disease Braak 3 and LBD Braak 2, that patient would receive a primary pathology classification of FTLD-TDP B, along with secondary pathology codes for MND, Alzheimer's disease, and LBD (present), and tau (absent).

Genetic Analysis

A subgroup of 49 participants received genetic testing as part of their research protocol. For these patients, we coded available information regarding APOE and tau haplotype status as well as the presence of an expansion in the C9orf72 gene and of any mutation in Alzheimer's disease autosomal dominant gene (APP, PSEN1, and PSEN2), and in any of the other most common FTLD autosomal dominant genes [FUS, GRN, MAPT, and TARDBP (encoding TDP)].

Statistical Analysis

All analyses were conducted using SPSS version 25. First, we determined the frequencies of hallucinations and delusions and all symptom subtypes across primary pathological diagnoses. Then, we conducted Fisher's exact chi-squared tests of independence to compare the frequencies of each symptom, both among the four major pathological categories detailed above and then among specific pathological diagnoses. In a secondary analysis, we used chi-square tests to determine if the presence of a co-pathology influenced whether patients with a specific primary neuropathological diagnosis were more likely to have a particular psychosis subtype (e.g. in all patients with FTLD-TDP-A who had LBD co-pathology, we compared the frequency of patients who had persecutory delusions to those who did not). We performed logistic regressions with the four primary pathology categories to assess their effect on specific psychotic symptoms. For each psychosis subtype, we used a single model which included: (i) Alzheimer's disease severity, as measured by the Alzheimer's disease NIA-AA ADNC likelihood (low, intermediate, or high); (ii) Parkinson's disease Braak staging [grouped into Braak 1–2 (brainstem-predominant), Braak 3–4 (transitional limbic) and Braak 5–6 (diffuse neocortical)]; and (iii) TDP presence (none, limbic only, or diffuse), controlling for gender, level of education, and age at death. We corrected for multiple pairwise testing analyses according to the B-Y method (Benjamini and Yekutieli, 2001).

Data Availability

The data that support the findings of this study are not publicly available because they contain information that could compromise the privacy of research participants, but are available on request from the corresponding author.