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

Abstract and Introduction


Although psychosis is a defining feature of Lewy body disease, psychotic symptoms occur in a subset of patients with every major neurodegenerative disease. Few studies, however, have compared disease-related rates of psychosis prevalence in a large autopsy-based cohort, and it remains unclear how diseases differ with respect to the nature or content of the psychosis. We conducted a retrospective chart review of 372 patients with autopsy-confirmed neurodegenerative pathology: 111 with Alzheimer's disease, 59 with Lewy body disease and concomitant Alzheimer's disease, 133 with frontotemporal lobar degeneration (FTLD) with tau inclusions (including progressive supranuclear palsy, corticobasal degeneration or Pick's disease), and 69 with FTLD and TDP inclusions (FTLD-TDP, including types A–C). Psychosis content was classified by subtype, and the frequency of each subtype was compared among pathological diagnoses using logistic regression. A total of 111 of 372 patients had psychosis. Compared to other groups, patients with Lewy body disease/Alzheimer's disease pathology were significantly more likely to have hallucinations and were more likely to have more than one subtype of hallucination. Patients with Braak Parkinson stage 5–6 Lewy body disease were significantly more likely than those with no Lewy body disease to have visual hallucinations of misperception, peripheral hallucinations, hallucinations that moved, hallucinations of people/animals/objects, as well as delusions regarding a place and delusions of misidentification. The feeling of a presence occurred significantly more frequently in patients with Lewy body disease/Alzheimer's disease than all other pathologies. Patients with FTLD-TDP were significantly more likely to have delusions, and for the delusions to occur in the first 3 years of the disease, when compared to patients with Alzheimer's disease and FTLD-tau, though rates were not significantly greater than patients with Lewy body disease/Alzheimer's disease. Paranoia occurred more frequently in the FTLD-TDP and Lewy body disease/Alzheimer's disease categories compared to patients with Alzheimer's disease or FTLD-tau. Patients with FTLD-TDP pathology had delusions of misidentification as frequently as patients with Lewy body disease/Alzheimer's disease, and were significantly more likely to have self-elevating delusions such as grandiosity and erotomania compared to patients with other pathologies including FTLD-tau. These data show that the nature and content of psychosis can provide meaningful information about the underlying neurodegenerative pathology, emphasizing the importance of characterizing patients' psychoses for prediction of the neuropathological diagnosis, regardless of a patient's clinical syndrome.


Neuropsychiatric symptoms, including psychosis, are common manifestations of neurodegenerative disorders (Lyketsos et al., 2001, 2012) and can often be the first sign of disease (Haddad and Benbow, 1992; Auning et al., 2011). Advancing our understanding of psychotic symptoms in patients with neurodegenerative disease is critical for clinical care, because studies have shown that people who have delusions may act on their false beliefs in a manner that can be harmful to themselves and their surroundings (Gilleen and David, 2005). Furthermore, psychosis is a major source of stress, anxiety and depression, placing a significant burden both on people suffering from the disorder and on their caregivers (Lyketsos et al., 2012). Psychosis is associated with earlier institutionalization and a higher cost of care (Herrmann et al., 2006). The low prevalence of psychosis in typically ageing cohorts suggests that most late-life psychotic symptoms are likely indicative of underlying neurodegeneration (Geda et al., 2008; Ehrenberg et al., 2018). However, studies clearly linking specific neuropathologies with psychotic symptoms are lacking, and prevalence rates remain unclear.

Moreover, the phenomenology of psychosis in neurodegenerative disease has implications for understanding both disease mechanisms and the neural basis of psychosis. Patients with psychiatric, neurodegenerative, and eye disease show contrasting hallucination patterns and content, suggesting diverse underlying biological and physiological substrates (Dudley et al., 2019). Current medical management of psychosis in neurodegenerative disease tends to treat all different subtypes of delusions and hallucinations as a general problem in which cognition deviates from reality. However, this approach is based on the assumption that psychotic symptoms arise from a common underlying brain dysfunction, and thus are unlikely to show predictable content variability across diseases—an assumption that is not supported by existing clinical studies in patients with neurodegenerative disorders.

Hallucinations are a form of psychosis defined as a lived sensory experience in the absence of a sensory stimulus. Hallucinations are one of the core clinical diagnostic criteria of dementia with Lewy bodies syndrome (McKeith et al., 2017). According to a systematic meta-analysis, hallucinations occur in 13–16% of patients with Alzheimer-type dementia syndrome (Alzheimer's disease dementia) (Zhao et al., 2016). Another study found that visual, auditory and tactile hallucinations occurred in 36% of patients with behavioural variant frontotemporal dementia syndrome (bvFTD) who carried an expansion in one of the most common FTD-causing genes, C9orf72, compared to 17% of bvFTD non-carriers (Devenney et al., 2017). In dementia with Lewy bodies, visual hallucinations of people and those of non-human objects may arise from distinct neural origins (Nagahama et al., 2007, 2010). One theory of hallucinations is that all hallucinations share a common neural network that includes the right superior temporal sulcus, while the specific sensory modality and content of the hallucination relates to connections between that network and other sensory networks (Kim et al., 2019).

Delusions are another form of psychosis and are defined as 'fixed beliefs that are not amenable to change in light of conflicting evidence' (American Psychiatric Association, 2013). Up to 35% of patients with Alzheimer's disease dementia have delusions (Zhao et al., 2016). Delusions were the presenting neuropsychiatric symptom in 21% of patients with bvFTD and 18% of patients with FTD and motor neuron disease (FTD-MND) with an expansion in C9orf72 (Sha et al., 2012). One neuropsychological theory of delusions proposes a two-factor hypothesis whereby a delusion requires (i) a neuropsychological impairment that leads to the formation of the false belief, in addition to (ii) an impairment in processes that would normally lead to the rejection of the belief in question (Coltheart, 2010). This hypothesis suggests that the first impairment, which dictates the nature or content of the delusion, could be disease-specific, unlike the second impairment, which leads to the general fixation and persistence of the false belief, and is a process likely common to all conditions in which delusions manifest clinically. As an example of the disease specificity of delusion content, the delusions associated with the C9orf72 expansion can be grandiose (Shinagawa et al., 2015). In contrast, the delusions associated with Alzheimer's disease dementia are often of a paranoid nature, such as delusions of theft or persecution, and may be associated with volume loss in the right hippocampus (Geroldi et al., 2000). One factor analysis of psychotic symptoms in clinically defined dementia with Lewy bodies yielded four clusters: (i) misidentification of people and reduplication of people and places; (ii) belief that absent or deceased relatives are in the house; (iii) visual hallucinations of non-human objects; and (iv) visual hallucinations of people (Nagahama et al., 2007, 2010).

If delusions and hallucinations differ based on a patient's underlying neuropathology, then the content of the psychosis could have a predictive role, providing clinicians with valuable assistance in differential diagnosis. Such clinical tools are increasingly important in an era when pathology-specific pharmacological interventions are being designed and tested. The objective of this study was to assess the rates of specific types of psychosis content found in each major disease category in a large autopsied cohort of patients with neurodegenerative disease. Specifically, we hypothesized that distinct types and content of delusions and hallucinations would appear in patients with different neurodegenerative conditions.