Exploring Psychosis in Neurodegenerative Dementia: Connecting Symptoms to Neurobiology

Over a century ago, the clinical psychiatrist and neuroanatomist Alois Alzheimer presented the case of a middle-aged woman who experienced late-life paranoia, auditory hallucinations, sleep disturbance, and progressive memory loss over the five years leading up to her death [1, 2]. In his report, Alzheimer gave a detailed description of how her disease started with a “strong feeling of jealousy towards her husband” and that at times “she felt someone wanted to kill her.” He also described occasional auditory hallucinations of a child calling to her alongside periods of agitation and intense anxiety [3]. These psychotic symptoms were accompanied by pervasive memory impairment and on autopsy, Alzheimer noted distinctive plaques and neurofibrillary tangles on brain histology. This initial description continues to resonate today, defining the classic clinical and pathologic markers of the most common neurodegenerative disease worldwide, Alzheimer’s disease (AD).

While Alzheimer is remembered primarily for his description of the amyloid-beta plaques and tau tangles that define the pathology of AD, his description of the psychotic phenomena experienced by his patient is especially prescient in light of the review by Cressot et al. [4]. Cressot et al. highlight the importance of understanding and characterizing psychotic experiences in neurodegenerative dementia, with a focus on AD, frontotemporal degeneration (FTD), and dementia with Lewy bodies (DLB). They emphasize the core role that psychotic phenomena can play in these illnesses and the importance of careful clinical assessment, as modeled by Alzheimer a century ago, in guiding diagnosis and management.

Cressot et al. [4] provide a thorough, critical analysis of the literature, describing the epidemiology and phenomenology of psychosis in neurodegenerative dementia. They estimate that while prevalence rates vary widely in the literature, up to 54% of patients with AD, 74% of patients with DLB, and 42% of patients with FTD may experience psychotic symptoms. The authors carefully review a variety of specific psychotic experiences with an emphasis on those that help discriminate between syndromes, aiding clinicians in differentiating AD, FTD, or DLB from each other and from primary psychiatric disorders (PPD). Misidentification delusions (duplication of self, others, or the environment) are noted to be most associated with DLB, whereas paranoid delusions are noted to be most associated with AD. Grandiose and erotomania delusions are described as relatively rare, occurring in less than 10% of dementia patients with the exception of those with TDP-43 positive FTD. Somatic delusions (persistent false beliefs concerning body functioning) are also noted to be rare in AD and DLB but common in one of the FTD language variants, semantic variant primary progressive aphasia, where they occur in up to 40% of early-stage patients. Across dementia subtypes, visual hallucinations are noted to be most common, followed by auditory hallucinations. Hallucinations are reported to occur predominately in DLB; however, the authors again point out that a subset of FTD patients with C9orf72 mutations and TDP-43 pathology experience relatively high rates of hallucinations. In addition to visual and auditory hallucinations, Cressot et al. [4] describe minor phenomena (illusions, passage hallucinations, sense of presence, etc.) which are characteristic of DLB but largely absent in other forms of dementia and PPD. They conclude with a call for developing standardized and validated assessment tools to aid in capturing psychotic symptoms in these disorders, which, when combined with emerging biomarkers, may provide an opportunity for earlier diagnosis and treatment.

This review by Cressot et al. [4] brings to mind several core concepts critical to the future of transdiagnostic understanding and treatment of psychosis. First, by clarifying the neurobiology underlying psychotic symptoms in dementia, significant insights into primary psychiatric disease may be possible. For instance, in AD, the hippocampus is well established as a focal point of pathology, with evidence that both cognitive and psychotic symptoms emerge from dysfunction in hippocampal networks [5]. Similarly, in schizophrenia, hippocampal networks have been implicated in cognitive and psychotic symptoms [6]. Further delineation of the specific hippocampal networks implicated in psychotic symptoms in both disorders may pave the way for novel, targeted therapies.

In addition, the recognition that specific types of pathology (alpha-synuclein, TDP-43, etc.) are associated with high rates of psychosis suggests that it is not only the location of neural network dysfunction but also the type of protein aggregation that contributes to psychotic symptoms. TDP-43 pathology has been linked to psychosis in FTD and amyotrophic lateral sclerosis [7]. Interestingly, TDP-43 pathology has also been identified in the hippocampus of patients with bipolar disorder and schizophrenia, as well as in more common dementia syndromes like AD, DLB, and Parkinson’s disease (PD) [8]. This suggests that future biomarkers and therapies targeting TDP-43 pathology may have significant transdiagnostic potential.

Finally, Cressot et al.’s careful description of the diverse psychotic phenomena experienced by patients with dementia highlights the importance of developing tools to better elicit psychotic symptoms in neurodegenerative conditions [4]. The authors cite the Neuropsychiatric Inventory as the most common assessment tool in dementia studies; however, the Neuropsychiatric Inventory distills psychosis down to the presence or absence of symptoms along with a severity rating. Given the phenomenological differences across dementia subtypes and PPD, more nuanced tools are needed. The enhanced Scale for the Assessment of Positive Symptoms in PD (eSAPS-PD) could serve as a model for disease-specific psychosis screening tools.

While scientific advancements have brought us within reach of targeted, disease-modifying therapies, and disease-specific biomarkers Cressot et al.’s review reminds us that a skilled clinical interview, as modeled by Alzheimer a century ago, remains critical in diagnosing and guiding treatment of psychosis in neurodegenerative disease.