Hyperorality in Frontotemporal Dementia: Cognitive and Psychiatric Symptom Profiles in Early-Stage Disease

Abstract

Hyperorality is a distinctive feature of the behavioral variant of frontotemporal dementia (bvFTD), but little is known about its significance in early-stage disease. This study examined the cognitive and psychiatric symptom profiles associated with hyperorality, using data from subjects with early-stage bvFTD enrolled in Alzheimer’s Disease Research Centers. We found that hyperorality was not associated with cognitive performance, but was associated with psychosis, elation, and disinhibition. Hyperorality may share neurobiology with a subset of early psychiatric symptoms, a finding which could help identify targets for future treatment.

INTRODUCTION

The behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome characterized by progressive impairments in judgment, temperament, conduct, and cognition. Hyperorality is observed in over half of individuals with bvFTD and includes altered food preferences, binge eating, increased consumption of substances like alcohol or cigarettes, and oral exploration of inedible objects [1, 2]. While not universal in bvFTD, when present it facilitates differential diagnosis from neurodegenerative diseases like Alzheimer’s disease (AD) [3, 4]. The view has been put forward that the prominence of abnormal eating behaviors in bvFTD relates to executive dysfunction [5]. While the neuropathologic and physiologic underpinnings of hyperorality in bvFTD remain to be elucidated, atrophy in the cingulate cortices, thalami, orbitofrontal cortex, right anterior insula, and cerebellum have been implicated [6–8]. Hypothalamic degeneration and disintegration of network connections between the hypothalamus and orbitofrontal cortex have also been associated with hyperorality in bvFTD [9]. In addition, elevated levels of peripheral hormones like agouti-related peptide (AgRP) have been observed in bvFTD patients with hyperorality [9]. Given the neuroanatomic and physiologic correlates of hyperorality in FTD, it is reasonable to anticipate specific cognitive and behavioral profiles. Studies examining cognitive profiles of hyperorality in bvFTD are limited; analysis in a small sample found that the patients with hyperorality did not differ from those without hyperorality on measures of language, visuospatial skills, verbal/nonverbal memory, attention, or executive function, though they had worse behavioral and functional impairments and higher rates of neuropsychiatric symptoms(NPS)[8].

Given this background, we examined the neuropsychological profiles of bvFTD patients with and without hyperorality in a large national sample. The hypotheses were: 1) cognitive performance does not differ in those with and without hyperorality and 2) NPS, particularly psychosis and disinhibition, will be associated with hyperorality. Based on earlier studies, we anticipated there would be no association between hyperorality and cognition, which would suggest hyperorality is a manifestation of disruptions in specific neural networks due to patterns of neurodegeneration rather than a product of cognitive impairment. The proposal of association between hyperorality and NPS relates to the shared neural networks, which include the prefrontal and orbitofrontal circuits.

METHODS

Study sample

Data are from the Uniform Data Set (UDS) May 2021 data freeze maintained by the National Alzheimer’s Coordinating Center (NACC) [10]. Data included 1,707 subjects with a primary clinical diagnosis of bvFTD. Subjects with comorbid conditions that may influence eating behavior, cognitive function, or psychiatric status were excluded—these conditions include bipolar disorder, schizophrenia, alcohol abuse, substance abuse, traumatic brain injury, seizures, thyroid disease, B12 deficiency, macro or microhemorrhage, HIV, hydrocephalus, and Parkinson’s disease [8]. We did not include study visits after December 2019 in order to avoid virtual assessments during the COVID-19 pandemic with inconsistently collected neuropsychological data. Data analysis was limited to subjects in the early stages of illness with a CDR^® plus NACC FTLD Behavior & Language Domains global score (CDR plus NACC FTLD) less than or equal to 1. The final study population consisted of 458 subjects, 206 of whom had data available regarding the presence or absence of hyperorality [11–13]. The hyperorality variable was drawn from the UDS FTLD module. This module was implemented to capture clinical characteristics of subjects with FTD. The hyperorality variable was drawn from Form B9F–Clinical PPA and bvFTD Features. Hyperorality was recorded as present where the hyperorality variable was marked as “definitely present”, and otherwise as absent.

Neuropsychological data were also derived from questionnaires in the UDS FTLD module. Behavioral scales included measures of self-monitoring, empathetic concern, perspective taking, behavioral inhibition, social norms, geriatric depression, CDR behavior subscale, and social behavior observer check list. Cognitive domains were assessed using tests of processing speed (Trail Making Test Part A and Digit Symbol Substitution Test), language (Boston Naming, category fluency), executive functioning (Trail Making Test B minus Trail Making Test A, Digit Span Backward), memory (Logical Memory – Immediate and Delayed), and attention (Digit Span Forward). See the Supplementary Material for a description of each of the behavioral scales and cognitive tests. Data from the Neuropsychiatric Inventory Questionnaire (NPI-Q) captured the following neuropsychiatric states: depression, anxiety, psychosis, apathy, disinhibition, irritability, elation, and sleep disturbance/nighttime behaviors. The NPIQ is a widely used and well validated questionnaire used to assess psychiatric symptoms in subjects with various types of dementia, including bvFTD [14–18]. Psychiatric states were defined as dichotomous variables based on the presence or absence of symptoms. We also performed a deeper analysis, examining associations between NPS severity and hyperorality.

Pathology data were available for a small subset of the subjects. Frontotemporal lobar degeneration (FTLD) pathology was defined by the presence of tau, TDP-43, FUS, ubiquitin or p62 positive inclusion bodies. AD pathology was based on Thal phase for amyloid plaques, Braak stage for neurofibrillary degeneration, density of neocortical neuritic plaques, AD neuropathologic change score and density of diffuse plaques.

Statistical methods

Differences in baseline characteristics and clinical outcomes were compared using t-tests for continuous variables and Pearson χ² tests for categorical variables. Statistical significance was based on Bonferroni corrected alpha levels to account for multiple comparisons. p values less than 0.05 divided by the number of tests performed were considered significant. STATA SE 17 (StataCorp LP, College Station, TX) was used for all analyses.

RESULTS

Demographics

Sample characteristics are shown in Table 1. Subjects with and without hyperorality were similar in terms of age, sex, race, MMSE, CDR, and CDR plus NACC FTLD.

Table 1.

Demographic characteristics

	HYP− (n = 133)	HYP+ (n = 73)	t-value or χ2*	Effect Size**	*** p
	mean (SD)	mean (SD)
Age (y)	62.0 (8.9)	63.5 (8.1)	–1.1	0.18	0.26
Sex (% Men ∣ % Women)	64.7 |35.3	71.2 |28.8	2.1	0.07	0.34
Race (% white)	94.0	91.8	0.9	0.10	0.34
Education level (y)	15.7 (2.7)	16.7 (3.2)	–2.4	0.34	0.02
MMSE	25.0 (4.2)	23.7 (5.3)	1.0	0.26	0.31
CDR Global (mean)	0.69 (0.27)	0.76 (0.25)	1.9	0.27	0.06
CDR-FTLD (mean)	0.94 (0.16)	0.96 (0.14)	–0.8	0.13	0.40

^∗t-values for continuous variables, χ² for categorical variables.

^∗∗Cohen’s d for continuous variables, phi coefficient for categorical variables.

^***statistical significance based on Bonferroni adjusted alpha level of 0.007 (0.05/7).

Pathology data were available for only 13% of subjects. Of those with pathology data, 39% had only FTD pathology, 46% had both FTD and AD pathology, and15%hadonlyADpathology.Pathologytype was not associated with hyperorality.

Neuropsychological variables

Neuropsychological scores are shown in Table 2. Subjects with and without hyperorality showed no difference with respect to scales assessing empathetic concern, perspective taking, behavioral inhibition, adherence to social norms, global deficits, or social behavior observer checklist. Subjects with hyperorality performed more poorly on a self-monitoring scale (20.1 versus 26.7, p<0.001).

Table 2.

Cognitive and social behavioral scores for bvFTD patients with (HYP+) and without hyperorality (HYP–)

Cognitive Domain	Test	Test Index Used	HYP–mean (SD)	HYP+mean (SD)	t-value/χ2*	Effect Size**	*** p
Processing Speed	TMT-A	Completion time (s)	51.7 (29.3)	45.4 (21.9)	1.6	0.24	0.12
	DS	Total in 90s	35.1 (14.8)	37.6 (15.6)	–0.6	0.16	0.55
Language	BNT	Total correct	22.7 (7.1)	20.7 (9.4)	0.9	0.24	0.36
	Category Fluency	Animal cued	12.8 (6.7)	13.8 (7.2)	–1.0	0.14	0.34
		Vegetable cued	8.2 (4.4)	8.0 (4.9)	0.4	0.04	0.68
Executive Functioning	TMT-B – TMT-A	Difference in completion time (s)	100.1 (74.0)	95.6 (80.2)	0.4	0.06	0.71
	DSB	Longest backward span	3.7 (1.8)	3.7 (1.5)	–0.03	0.0	0.98
Memory	LM Immediate	Total story units	7.9 (4.9)	6.8 (5.0)	0.8	0.22	0.42
	LM Delayed	Total story units	6.2 (5.0)	5.8 (5.1)	0.3	0.08	0.76
Attention	DSF	Longest forward span	5.8 (1.4)	6.0 (1.8)	–0.3	0.12	0.76
Social Behavioral Measures	Self-Monitoring Scale		26.7 (11.9)	20.1 (10.5)	3.8	0.59	<0.001
	IRI – Empathetic Concern		21.3 (6.5)	21.4 (6.7)	–0.04	0.02	0.97
	IRI – Perspective-Taking		15.7 (6.0)	14.1 (4.9)	1.9	0.29	0.06
	BIS		17.5 (3.8)	17.0 (3.8)	0.86	0.13	0.39
	Social Norms Questionnaire		17.7 (3.0)	17.6 (2.4)	0.11	0.04	0.91
	GDS		3.2 (3.6)	3.1 (3.3)	0.23	0.03	0.82
	CDR Behavioral Subscale		1.1 (0.47)	1.3 (0.6)	–2.1	0.35	0.03
	Social Behavior Observer Checklist		7.4 (7.8)	9.6 (11.0)	–1.6	0.23	0.11

^∗t-values for continuous variables, x² for categorical variables.

^**Cohen’s d.

^***statistical significance based on Bonferroni adjusted alpha level of 0.003 (0.05/18).

Table 2 shows performance on each cognitive domain based on hyperorality status. There were no differences in performance on tasks of processing speed, language, executive functioning, memory, or attention in those with and without hyperorality.

Neuropsychiatric symptoms

Table 3 shows associations of neuropsychiatric states with hyperorality. Psychosis (29.6% versus 12.0%, p=0.002) and elation were more common in subjects with hyperorality (36.1% versus 17.6%, p=0.004) as was disinhibition (82.0% versus 51.2%, p<0.001). There were no associations between hyperorality and agitation, depression, anxiety, apathy, irritability, or sleep disturbance. Of note, 85% of subjects with hyperorality had either psychosis, disinhibition, orelation.34%ofsubjectswithhyperorality had disinhibition and elation, 25% had psychosis and disinhibition, 12% had psychosis and elation, and 11% had psychosis, disinhibition, and elation. We also tested for associations between NPS severity and hyperorality. When accounting for NPS severity, disinhibition remained more common (χ² =18.9, p<0.001); however, psychosis (χ² =9.7, p=0.02) and elation (χ² =10.5, p=0.02) were no longer considered statistically more common at a Bonferroni corrected p-value threshold of 0.006 (Supplementary Table 1).

Table 3.

Neuropsychiatric symptoms

	HYP−	HYP+	χ2	Effect Size*	** p
	%	%
Psychosis	12.0	29.6	9.3	0.22	0.002
Agitation	41.3	51.4	1.9	0.1	0.17
Depression	48.0	38.9	1.5	0.09	0.22
Anxiety	43.6	42.3	0.03	0.01	0.86
Elation	17.6	36.1	8.5	0.21	0.004
Apathy	73.0	80.6	1.4	0.08	0.23
Disinhibition	51.2	82.0	18.4	0.31	<0.001
Irritability	52.8	54.2	0.03	0.01	0.85
Sleep Disturbance	33.3	47.1	3.6	0.14	0.06

^∗Phi coefficient.

^**statistical significance based on Bonferroni adjusted alpha level of 0.006 (0.05/9).

DISCUSSION

This study examined the neuropsychological profiles of bvFTD subjects and showed that cognitive performance across domains of processing speed, language, executive functioning, memory, and attention did not differ based on hyperorality status. bvFTD patients with hyperorality had lower self-monitoring scores. There were no other differences in cognitive or behavioral domains. This finding is consistent with observations in smaller studies assessing the neuropsychological performance of bvFTD patients with and without hyperorality [8]. These findings support the theory that hyperorality originates from differences in neurodegeneration patterns, with impacts on specific structures giving rise to a bvFTD phenotype that differs behaviorally but not cognitively from those without hyperorality.

This study also sheds new insights on the ways in which NPS co-occur in subjects with hyperorality. Specifically, psychosis, elation, and disinhibition were all associated with hyperorality. While prior studies of neuropsychiatric states in bvFTD subjects found increases in euphoria, apathy, disinhibition, and aberrant motor and sleep behaviors, they did not find the same pattern of NPS described in this study [8]. In this study, 85% of subjects with hyperorality showed some combination of psychosis, disinhibition, and elation. While preliminary, these findings suggest that hyperorality may share neurobiological underpinnings with certain NPS [8, 19–21]. Interestingly, in other disorders with prominent overeating behaviors like Prader-Willi-Syndrome, abnormalities in the limbic system and striatal circuits have been observed in association with obsessive-compulsive behaviors, psychosis, and disinhibition[22]. Similarly, in binge-eating disorder, orbitofrontal-insular-striatal circuit hypoactivity has been implicated [23]. Obsessive-compulsive symptoms were not captured by the NPI-Q used to assess psychiatric states in this study. Therefore, more studies are needed to examine associations between obsessive-compulsive symptoms and hyperorality in bvFTD, their neuroanatomical correlates, and overlaps with syndromes like Prader-Willi.

The implications of these observation are significant in several ways. First, prior work in subjects with AD has shown that certain NPS clusters are associated with variable rates of cognitive and functional decline [24, 25]. While this study is preliminary and does not involve a formal cluster analysis, the association of a group of particular NPS with hyperorality is intriguing. Future studies are needed to clarify if the pattern of NPS clusters observed in AD is true for subjects with bvFTD. Secondly, prior studies have correlated patterns of neuroanatomic change in FTD with specific NPS [26, 27]. This study does not involve analysis of atrophy patterns or patterns of functional connectivity associated with hyperorality; however, our findings suggest that future work in this area may help personalize treatment of hyperorality and other associated NPS. There are few therapeutic options at present for patients with bvFTD and hyperorality. Behavioral interventions like portion control, supervised eating, and feeding often fail to fully control behavior. When pharmacotherapy is needed, agents like SSRIs and trazodone are often employed; however, their impact on hyperorality is limited. Other agents like topiramate can be effective in certain cases but have not been systematically studied [28–33]. These pharmacologic interventions were developed to treat primary eating disorders in younger patients and have limited efficacy. In addition, they focus on symptoms and not the specific neurobiological mechanisms underlying hyperorality and other NPS [34]. Targeted therapies directed at the neurobiology of hyperorality and related NPS could benefit individuals with bvFTD in a significant [35–37].

This study benefited from the use of a large multisite database of subjects with bvFTD. However, this is a retrospective cohort in which hyperorality is not richly described, and necessarily reliant on clinical diagnosis of bvFTD rather than pathological diagnosis. However, most cases in the study sample for whom autopsy data were available had FTLD pathology. Hyperorality was treated as a dichotomous variable in this study, but we acknowledge that hyperorality severity is an important consideration. This is a limitation of the available data. An exploratory analysis included the ‘questionable’ category of hyperorality defined in the NACC data. This approach did not materially change the associations observed (Supplementary Tables 2–4). In this analysis, the ‘questionable’ hyperorality group was more similar to those without hyperorality than to those with ‘definite’ hyperorality. This suggests that the utility of designating a ‘questionable’ hyperorality category may be limited, and that more thorough clinical characterization of hyperorality with tools like the Appetite and Eating Habits Questionnaire (APEHQ), the DAPHNE scale or Cambridge Behavioral Inventory are preferred [4, 38, 39]. Future studies will benefit from measures that grade the severity of hyperorality. Finally, the study population consisted predominantly of white subjects and findings may not generalize to other ethnocultural groups.

Conclusion

This study provides preliminary insights into the cognitive, behavioral, and psychiatric profiles of subjects with bvFTD and hyperorality. The findings suggest that certain NPS including psychosis, disinhibition, and elation may have an association with hyperorality, and this may indicate shared neurobiological substrates. These findings will need to be buttressed and expanded upon in future studies that provide data on structural and functional neuroanatomic correlates of hyperorality and other NPS symptom clusters. Work of this type has the potential to open new opportunities for targeting hyperorality with novel non-pharmacologic techniques like non-invasive brain stimulation. While bvFTD is a relentlessly progressive neurodegenerative condition, our study highlights opportunities to enhance our understanding of the disease in order to develop pathophysiologically rational therapies for difficult clinical states.