Narcissistic Personality Disorder as Prodromal Feature of Early-Onset,GRN -Positive bvFTD: A Case Report

INTRODUCTION

Behavioral and psychiatric features can be observed in a wide range of neurodegenerative diseases at both late and early stages [1, 2]. In the latter scenario these can be erroneously attributed to a primary psychiatric disease, resulting in a delay in the diagnosis [1]. In fact, 50% of these patients are initially diagnosed with a primary psychiatric disorder [3].

Early-stage behavioral variant frontotemporal dementia (bvFTD) proves especially challenging to discriminate from psychiatric diseases such as bipolar disorder, major depressive disorder, obsessive-compulsive disorder, schizophrenia, catatonia, and personality disorders [4]. Early decline in social conduct with behavioral changes such as apathy, disinhibition, and irritability as well as stereotyped movements, repetitive gestures and a shift in eating habits have been described as typical early-onset features of both genetic and sporadic bvFTD [5–7]. Additional attributes include emotional blunting, general loss of insight, distractibility, loss of volition and relative sparing of memory. The onset is often subtle and involves mild changes in personality and values. These can be misunderstood by relatives so that patients get referred to a specialist only later. Furthermore, these very early stages of bvFTD can be misdiagnosed even by expert physicians [4].

Very few cases of patients diagnosed with a personality disorder preceding bvFTD have been reported. Borderline personality disorder and narcissistic personality disorder (NPD) have been described to anticipate the diagnosis of bvFTD by 5 years [8] and decades [9], respectively. However, none of these patients had a diagnosis of bvFTD confirmed by pathology or genetic screening.

We report the first case of a GRN-mutation positive patient who was diagnosed with NPD seven years before being referred to neurological examination. We hope that this case report will be helpful in widening the known spectrum of the prodromal features of bvFTD and its genotype-phenotype correlations.

MATERIAL AND METHODS

RESULTS

MRI and CSF studies

Brain MRI (Fig.  1) showed diffuse enlargement of the convexity sulci and of the ventricular complexes, frontal and parietal bilateral atrophy (Global Cortical Atrophy score: 2 [11]; Koedam score: 2 [12] and bilateral hippocampal atrophy (Middle Temporal Atrophy score: 2) [13]. CSF biomarkers were negative for Alzheimer’s disease (Aβ₄₂: 830 g/mL; total tau: 416 /mL; p-tau181 : 23.10 pg/mL) and indicated a Suspected Non Alzheimer Pathology (SNAP) [14].

OPEN IN VIEWER

Fig. 1

Representative MRI T2 FLAIR weighted images in axial (A, B, C) and coronal slices (D) show fronto-temporal cortical atrophy. Hippocampal structures appear moderately atrophic at coronal FLAIR (D).

Genetic analysis

Finally, genetic analysis (pedigree of the patient in Fig.  2) confirmed the clinical suspect of bvFTD [5]. Next generation sequencing analysis revealed the pathogenic variant c.709-2A>T at heterozygous state in the GRN gene (NM_002087.4). It is predicted to disrupt the highly conserved acceptor splice site of intron 7. This variant has previously been described as disease disease-causing mutation for FTD [15, 16].The proband’s mother and brother refused to perform genetic testing for evaluation of the GRN mutation.

OPEN IN VIEWER

Fig. 2

The pedigree of the family.

DISCUSSION

This is the first reported case of genetically defined bvFTD-caused NPD. The clinical spectrum of prodromal bvFTD encompasses several clinical features often leading to misdiagnosis of primary psychiatric diseases [1, 4]. This occurred to our patient, who had received a diagnosis of NPD 5 years before being referred to our outpatient service.

According to DSM-5, NPD can be diagnosed when a patient has an inflated sense of their own importance, often fantasizing about unlimited success, power, brilliance, or perfect love or exaggerating their achievements. They may believe that they are unique or exceptional and only deserve to be associated with other people (or institutions) who share a high status or are equally “special.” They crave excessive admiration and may feel entitled to certain privileges; they re-orient their behavior to obtain others’ praise. They may also exploit others for their own benefit, lack empathy, and display arrogant or haughty behaviors. They are often envious of others, or they believe that others are envious of them [17–19].

Both personality disorders and early-stage bvFTD involve subtle change in personality. In particular, narcissistic personalities and bvFTD may share traits like puerilism, selfishness, disregard for others [4]. However, some of these features are distinctive of one rather than the other condition, such as the presence of an exaggerated sense of self-grandiosity, which is absent in bvFTD. Other types of behavioral alterations can be revealed to be different in the two conditions if investigated from a neuropsychological viewpoint. For example, despite sharing the lack of empathy, individuals with bvFTD exhibit impairments in cognitive empathy [20], whereas those with NPD demonstrate deficiencies in emotional empathy [21].

Finally, some actions can be present in both NPD and bvFTD but are explained by different drives. For instance, patients with bvFTD may demonstrate acquired antisocial behaviors, such as patients with NPD. Nevertheless, in bvFTD these behaviors are often impulsive and result from disinhibition rather than intentional aggression [22]. In bvFTD, disinhibition rather than a deep-seated need for admiration and validation is also at the basis of conducts that can be confounded with attention-seeking behavior, which is seen in NPD. These include inappropriate jokes, overfamiliarity, loud or disruptive actions, and unusual dressing.

Personality disorders have been reported only in very few cases as possible prodromal manifestations of bvFTD [8, 9]. In fact, an NPD diagnosis preceding the development of bvFTD features in a 73-year-old man has been reported only once [9]. The diagnosis of NPD was made retrospectively according to features that had been present in the patient since young adulthood. This led the authors to speculate whether this kind of long-lasting psychiatric feature could be reframed as prodromal features of a disease that would become overt only decades later. This was also the case with our patient: she showed minor behavioral disturbances since young adulthood that, in hindsight, already fell under the spectrum of the later-diagnosed NPD.

In the past, the concept of selective vulnerability was introduced to clarify why some networks are more susceptible to neurodegeneration, and why the same pathological process manifests in diverse clinical presentations among individuals [23]. Non-pathological personality traits such as high neuroticism [24, 25] and low conscientiousness were associated with dementia and mild cognitive impairment [25]. Environmental factors have been speculated to contribute to increased susceptibility to develop primary progressive aphasia [26], which belongs to the same neuropathological spectrum as bvFTD. It has been speculated that NPD and other affective psychiatric disorders could increase the neurobiological vulnerability for bvFTD [9].

A common biological framework for the shared clinical features between bvFTD and NPD has been suggested by neuroimaging studies, where both regional atrophy and connectivity alterations located in the fronto-temporal and insular cortices are relatively robust findings among the spectrum of both bvFTD and narcissistic behavioral traits [27–35].

Exploring the potential links between personality disorders and neurodegenerative conditions, it is worth noting that certain personality disorders like schizotypal, avoidant, obsessive-compulsive, histrionic, and narcissistic personality disorders have been linked to a higher risk of developing Alzheimer’s disease [36]. However, epidemiological evidence on the link between NPD and bvFTD has not been reported yet. More generally, no consensus on environmental psychosocial risk factors for the development of bvFTD has been reached [37–39]. A bipolar disorder-linked increase in the risk of developing a subsequent bvFTD [40] has been suggested. However, some cases of long-lasting bipolar disorder suggest that these findings could be biased by early presentations of bvFTD [40].

The possibility that premorbid personality disorders could have an influence in the clinical phenomenology of subsequent cognitive decline, i.e., the presence of a pathoplastic effect of personality, has also been previously studied in retrospective studies [41]. Despite the confusion between long-standing premorbid personality traits and transitory personality changes has hampered most of these studies [41], there is evidence of a moderate link between traits such as neuroticism and low tolerance towards frustration and later personality changes [42] and depression [43], respectively.

Life-long subtle neuropsychiatric traits such as reduction in empathy and flexibility were retrospectively demonstrated in C9orf72 carriers [44]. Impaired executive functions, attention and social cognition have been found to be present in pre-symptomatic GRN mutation carriers up to eight years before the onset of the full-blown disease [45–47]. An abnormally high load of white matter hyperintensities have been seen in these asymptomatic carriers [48] This suggests that neurodegeneration in bvFTD starts long before the features of the disease become overt. However, GRN-mutation carriers who develop bvFTD have not been associated yet with specific clinical symptoms or pre-morbid personality traits [45, 46].

Despite having received a diagnosis of NPD, our patient did not meet the DSM-5 criteria “D” for such diagnosis. This addresses an abnormal functioning of the patient in respect to the norms of their socio-cultural environment or developmental stage. The fact that the patient managed to conduct a relatively normal life in terms of social functioning before the later exacerbation of her behavioral traits should have been raised as a red flag for an alternative diagnosis. In fact, according to DSM-5, typical personality disorders must be present since an earlier age. Deviations from these patterns of presentation should make the clinician aware that possible neurodegenerative diseases such as bvFTD should be included in the differential diagnosis.

Asymmetrical frontal brain atrophy with parietal involvement has been reported in GRN-mutation positive FTD [49, 50]. In fact, these features were present in our patient. The clinical correlate of these neuroimaging peculiarities has not been explained yet. Further cases of GRN-mutation positive bvFTD patients could clarify if this is related to particular psychiatric presentations. Another perplexing finding is the absence of a clear bvFTD diagnosis in the patient’s father. Nevertheless, considering that he passed away at the age of 72, it is plausible that this case represents an under-diagnosis. Of note, GRN-positive bvFTD is known for its high penetrance but relatively late onset, with an average age of onset at around 60 years old [51].

In conclusion, our case report confirms that unusual clinical features, secondary to underlying neurodegeneration, can manifest many years earlier than typical onset of bvFTD, resembling primary psychiatric disorders. Describing additional cases would help unravel whether the behavioral profile of these patients can be affected by the disease earlier than previously thought. Understanding these early manifestations is crucial for accurate diagnosis and management, as these patients could potentially benefit from early administration of targeted and new disease-modifying treatments.

AUTHOR CONTRIBUTIONS

Daniele Urso (Conceptualization; Investigation; Methodology; Project administration; Supervision; Writing – original draft; Writing – review & editing); Marco Michelutti (Conceptualization; Investigation; Methodology; Writing – original draft; Writing – review & editing); Valentina Gnoni (Writing – review & editing); Alessia Giugno (Writing – review & editing); Chiara Zecca (Data curation; Writing – review & editing); Davide Vilella (Writing – review & editing); Maria Accadia (Data curation; Writing – review & editing); Roberta Barone (Data curation; Writing – review & editing); Maria Teresa Dell’Abate (Data curation; Writing – review & editing); Roberto De Blasi (Writing – review & editing); Paolo Manganotti (Writing – review & editing); Giancarlo Logroscino (Conceptualization; Methodology; Project administration; Supervision; Writing – original draft; Writing – review & editing).