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


Our findings reveal that specific contents of hallucinations and delusions are preferentially associated with specific pathological diagnoses, and thus may reflect the anatomical and physiological differences among these conditions. Our analysis showed that patients with LBD/AD were more likely to have visual misperceptions, and hallucinations that are shapeless, peripheral and with images that moved, in addition to well-formed hallucinations, and also were more likely to experience the feeling of presence. Delusions of misidentification occured more frequently in patients with LBD/AD and patients with FTLD-TDP. Furthermore, patients with FTLD-TDP were more likely than those with any other pathology to report paranoid delusions, as well as delusions that were self-elevating, including grandiosity and erotomania. These results suggest that knowledge of delusion subtype may help differentiate patients with clinical FTD who have underlying FTLD-TDP from those who have FTLD-tau. Additionally, our results suggest that the neurobiology of psychosis in different neurodegenerative diseases may differ, which may have implications for future pharmacological treatments of dementia related psychosis. While there may be a core neural aetiology for all symptoms involving deviation from reality, if differences in psychosis content are reflective of divergent neurobiology, then future precision medicine treatments may also need to target the additional neural networks or neurotransmitters corresponding to that content.

Prior clinical studies have suggested that patients with different clinical syndromes display different subtypes of psychosis (Geroldi et al., 2000; Nagahama et al., 2007, 2010; Shinagawa et al., 2015). Our results confirm this relationship in a pathology-proven cohort. One hypothesis to explain this relationship posits that all patients with psychosis share a common anatomical network that makes them prone to deviate from reality, but it interacts with dysfunctions in other anatomical networks that are specific to each disease, thereby leading to disease-specific psychosis content (Coltheart, 2010; Kim et al., 2019). For example, Sellami and colleagues demonstrated that in a cohort of patients with genetic mutations known to cause FTLD, different mutations were associated with different patterns of cortical atrophy in those who displayed psychotic and other neuropsychiatric symptoms (Sellami et al., 2018). Interestingly, patients with the C9orf72 expansion who had delusions also had cortical atrophy in left frontal circuitry (Sellami et al., 2018), which may explain why we found a correlation between FTLD-TDP-B pathology, the presence of a C9orf72 expansion, and grandiose delusions. A previous investigation found grandiose delusions in 2 of 14 and 2 of 42 patients with bvFTD with and without the C9orf72 expansion, respectively (Devenney et al., 2017). Our findings also suggested that erotomania occurs more frequently in patients with GRN mutations, while Sellami et al. (2018) found that patients with GRN mutations who have delusions also have atrophy in anterior insular structures, which play a role in self-awareness. To our knowledge, this is the first report of erotomania in a patient with a GRN mutation. The literature for erotomania consists mostly of case reports in clinical Alzheimer's disease (Cipriani et al., 2012), though we did not find this in our autopsy-confirmed cohort. Not only does our data underline the association between FTLD-TDP pathology and self-elevating delusions, both grandiose and erotomanic, but also highlights the usefulness of this symptom in differentiating TDP from tau pathology in patients with an FTLD syndrome.

In addition to self-elevating delusions, we found a high occurrence of paranoia, and specifically delusions of intrusion, in patients with FTLD-TDP and in patients with mixed LBD/AD pathologies. Previous clinical studies have suggested that the frequency of persecutory delusions was up to 29% and 14% in patients with clinical bvFTD, with and without the C9orf72 expansion, respectively (Takada and Sha, 2012; Devenney et al., 2017). We confirm this finding, and highlight that paranoia is not exclusively a characteristic of Alzheimer's disease, as the literature in clinical studies seems to suggest (Geroldi et al., 2000; Nakatsuka et al., 2013, 2014), but should prompt clinicians to consider FTLD-TDP or LBD pathologies, especially when it occurs early after disease onset. The neurobiological source of paranoia remains unclear, although it may stem from dysfunction in the default mode network (DMN) (Huang et al., 2018), which can be affected in patients with LBD and was found to correlate with anxiety in patients with GRN mutations (Sellami et al., 2018). In the literature, delusional jealousy was found to be more prevalent in patients with clinically defined dementia with Lewy bodies (26.3%) as compared to patients with clinical Alzheimer's disease (5.5%) (Hashimoto et al., 2015). Patients with FTD were not included in that study. The association between the delusion of infidelity and bvFTD was reported in the literature in clinical series where genetic testing for the C9orf72 expansion was conducted (Takada and Sha, 2012; Shinagawa et al., 2015; Devenney et al., 2017). In our cohort, we found low occurrence of jealousy delusions in any diagnostic group. We acknowledge that the delusion of theft may have been underrepresented in our Alzheimer's disease sample because physicians may be less likely to document it in the chart as an important phenomenon, since, at least anecdotally, a large number of patients with Alzheimer's disease will believe at some point that someone is stealing from them, especially as they forget where they have placed their belongings.

Our findings show that both Parkinson's disease Braak 5–6 and the presence of an FTLD-TDP pathology were both independently predictive of misidentification delusions. In clinical studies without pathology confirmation, 15.8% of patients with clinical Alzheimer's disease, 16.6% of patients with dementia with Lewy bodies, and 8.3% of patients with semantic variant primary progressive aphasia were found to have some form of misidentification delusions (Harciarek and Kertesz, 2008). In a cohort of 41 patients with autopsy-confirmed LBD and 70 patients with autopsy-confirmed Alzheimer's disease, misidentification was not found to differ between the two groups (Ferman et al., 2013). However, that study did not look at the effect of contributing co-pathology, and the misidentification delusion was captured through a structured questionnaire that only asked whether the patient had difficulties recognizing family members, which could overlap with prosopagnosia and visual symptoms that are not necessarily fixed beliefs like delusions are. The neurobiological aetiology of misidentification delusions remains unclear; however, they may stem from the interplay between sensory circuitry and memory circuitry, as suggested by Hirstein and Ramachandran in the case of Capgras delusions (Hirstein and Ramachandran, 1997). We highlight the importance of considering both underlying FTLD-TDP and LBD pathologies on the diagnostic differential when evaluating patients who report misidentification delusions.

Patients with mixed LBD/AD pathology had a unique pattern of hallucinations, composed of hallucinations that are shapeless, occurring in the periphery of their visual field, and that were described as moving, in addition to visual misperceptions and the feeling of presence that occurred almost exclusively in patients with LBD/AD pathology. In a study examining the frequency of extracampine hallucinations, defined as a 'sense of a presence or fleeting movement in the absence of an associated visual percept' in patients with clinical Parkinson's disease, half of them reported this hallucination (Wood et al., 2015). However, it is unclear if some of the patients in that study would have described their hallucination as 'shadows'. In addition, our findings that non-formed hallucinations experienced in the periphery of the visual field and hallucinations of images that moved were significantly more likely to occur in patients with a Parkinson's disease Braak stage of 5–6 are consistent with other studies in clinical cohorts of patients with Parkinson's disease. These studies show evidence that minor hallucinations and illusions, including peripheral shadows and passage hallucinations, correlate with posterior cortical atrophy and hypometabolism on brain MRI and FDG-PET, respectively (Nishio et al., 2017). We also found that Parkinson's disease Braak 5–6 predicted hallucinations of people, animals and objects, which also occurred in other pathologies, albeit less frequently. The feeling of presence [leibhaftige Bewusstheit (Iseki et al., 2002)] was previously reported to occur at a 23% frequency in both patients with clinical dementia with Lewy bodies and patients with clinical Parkinson's disease. In a cohort of patients clinically diagnosed with dementia with Lewy bodies, the feeling of presence belonged to a cluster of symptoms that also included visual hallucinations, and was associated with hypoperfusion to the left ventral occipital gyrus and bilateral parietal lobes (Nagahama et al., 2010). In a cohort of patients clinically diagnosed with Parkinson's disease, the feeling of presence belonged to a cluster of symptoms including peripheral, minor and non-formed hallucinations as well as misperceptions, associating with posterior cortical atrophy and/or hypoperfusion (Nishio et al., 2017). To our knowledge, ours is the first clinicopathological analysis that establishes a statistically significant relationship between the feeling of presence and LBD pathology, especially in direct association with high Parkinson's disease Braak stages of 5–6. This finding underlines the importance of asking about this particular symptom when evaluating patients with cognitive decline in a clinical setting, because this may increase the chance of accurately detecting LBD pathology early on in the disease, when other defining symptoms of the pathology have not yet occurred.

Limitations and Conclusions

Our study has several limitations, including its retrospective nature. The descriptions of the delusions were extracted from physician notes, which may not have been complete or documented systematically. Moreover, there were small sample sizes for some of the delusion types, while a larger sample might have represented a broader selection of contributory primary or co-pathologies. Because the Memory and Aging Center at UCSF evaluates a large number of patients with FTD, the overall number of patients with FTLD pathologies may be over-represented in our sample; however, this would not have impacted the accuracy of the rates of psychosis we observed in these patients. Measures of disease severity such as a Mini-Mental State examination (MMSE) score were not captured by our chart review, in part because we did not consistently have an MMSE time locked with onset of psychosis, especially when the onset was many years prior to the first presentation of the patient to the centre for evaluation. Furthermore, our sample lacked a group of patients with LBD pathology without Alzheimer's disease, which may affect hallucination frequency as shown in clinically series without pathology confirmation (Lemstra et al., 2017). However, the differences in psychosis content remain valid. Our data also lacked information about concomitant neuropsychiatric symptoms such as anxiety and depression, therefore preventing additional analysis of how these other symptoms may affect the manifestation of psychosis. Finally, our study did not examine how regional distribution of pathology in the brain may mediate this relationship between pathology and psychotic symptom, thus this factor will be an important component of future investigations.

Collectively, our findings highlight the role of the nature and content of psychosis in predicting the underlying neuropathology of different neurodegenerative illnesses. It is important for clinicians who are evaluating patients with cognitive and behavioural changes to systematically ask about the content of their patients' fixed beliefs, as this may help with predicting their neuropathology ante-mortem, which is becoming increasingly more important as new pathology-specific therapies are emerging. Our findings also lay the groundwork for future research in which prospective systematic recording of the timing of psychotic symptoms over the disease course can be correlated with regional imaging markers of advancing neuropathology, in order to further refine the neuroanatomy and mechanistic neurophysiology of psychosis, which could lead to research into pharmacological and non-pharmacological interventions that more precisely target specific subtypes of psychosis by content.