Abstract
Bipolar disorder (BD) could represent a prodromal state of frontotemporal dementia (FTD). Two patients affected by lifelong BD with a progressive decline of cognitive functions, behavioral, and neurological signs, reached the early diagnosis of FTD before the age of 60. They were diagnosed as affected by primary progressive aphasia and FTD with parkinsonism, respectively. A diagnosis of FTD should therefore be taken into account, in case of unexpected cognitive and behavioral decline in patients with a long history of BD. Follow-up studies with genetic, neuropsychological, and neuroimaging markers of these BD/FTD patients could further explore some of the underlying association, opening new viable therapeutic options.
Keywords
INTRODUCTION
Psychiatric disorders have been associated with cognitive impairment [1] such as problems with working memory, attention, psychomotor speed, and verbal memory [2, 3]. Several studies have recognized an increased risk of developing dementia in patients affected by major psychiatric disorders like BD [4, 5]. Previous neuropsychological studies have documented a broad and increased pattern of cognitive impairment during manic and depressive episodes [6, 7] in comparison with euthymic state [8–10]. BD is most frequently associated with neurocognitive decline and dementia [11–13], and it was reported that 19.4% of older patients with BD fulfilled the DSM-IV criteria for dementia [5]. According to controlled prospective long-term studies, a diagnosis of dementia at readmission in patients discharged from psychiatric hospitals was more frequently performed in patients with depressive disorder or BD, compared to patients affected by other mental disorders [6].
Lebert and colleagues have supported an association between a clinical psychiatric history of BD and a specific type of dementia, whose clinical features were very similar to frontotemporal dementia (FTD) [14]. FTD includes three main clinical syndromes: the behavioral variant of FTD (bvFTD), semantic dementia (SD), and primary progressive aphasia (PPA) [15]. bvFTD is characterized by a constellation of behavioral and psychiatric symptoms such as lack of inhibition, euphoria, inappropriate jocularity, apathy, depression, emotional withdraw, irritability, and repetitive behavior, thus the differential diagnosis with psychiatric disorders like schizophrenia and affective disorders may be difficult [16]. Further, abnormal volumes and blood flow in frontal and temporal cortical areas are common neuropathological findings in both BD and FTD patients [17–20]. Taken together, these data provide evidence for shared pathophysiological pathways or risk factors of mood disorders and FTD. In the present brief case series, we described two patients affected by chronic BD ascertained in the Psychiatric Unit of the Department of Basic Medical Science, Neuroscience and Sense Organs, who later developed FTD, emphasizing the importance for psychiatrists to be aware of the clinical prodromal FTD symptoms.
CASE SERIES
Patient 1
A 56-year-old and highly educated (18 years) female with a long history of BD type I, firstly diagnosed by a trained psychiatrist according to Structured Clinical Interview for DSM-IV-TR [21], and with numerous hospitalizations in psychiatric units from the age of 20, was treated with several mood stabilizers, antidepressants, antipsychotics, and electroconvulsive therapy. Patient 1 had been employed until the age of 48. Family history was negative for neurological and psychiatric disorders. She was referred to the Neurodegenerative Disease Unit after the worsening of neurological signs and symptoms in the last 10 months before the admission. Based on clinical assessment, the most prominent symptom in the early phase of the disease was language impairment. Furthermore, she presented poor coordination, progressive aphasia, impairment in executive functions, dysgraphia, lack of inhibition, weight gain due to craving for sweet foods (biscuits and chocolates), decrease in personal hygiene, stereotyped motor behavior, and disturbances in recognizing familiar faces. These symptoms seemed to be independent from psychiatric conditions. Her affective symptoms were controlled with divalproex sodium 1000 mg/day, clozapine 200 mg/day, and clonazepam 2,5 mg/day, without improvement of other clinical signs and symptoms. At neurological examination, the medical team noticed plastic diffuse hypertonia and motor coordination dysfunction. Cerebrospinal fluid (CSF) cytology and chemical-physical characteristics were normal. Brain magnetic resonance imaging (MRI) showed signs of white matter gliosis in bilateral subcortical frontal areas and diffuse cortical atrophy in bilateral frontal and temporal areas. These imaging abnormalities represented a worsening of a previous MRI, performed two years before, when patient 1 was hospitalized for seizures with loss of consciousness and myoclonus to the limbs and she was discharged with diagnosis of “epileptic encephalopathy in subject affected by bipolar psychosis; minor left carotid stroke and ataxic syndrome”. Moreover, single photon emission computerized tomography (SPECT) imaging showed hypoperfusion in bilateral frontal and temporal areas. Furthermore, patient 1 underwent an extensive battery of neuropsychological tests presenting the most compromised outcomes in the domains of executive function, verbal memory, attention, and language skills (Table 1). Among these, the Mini-Mental State Examination (MMSE = 23.2/30) and the Frontal Assessment Battery (FAB = 8.45) showed only a mild impairment. Mutations of genes involved in FTD and others dementia were excluded [apolipoprotein E, amyloid precursor protein, presenilin 1 and 2, microtubule-associated protein tau, progranulin (GRN), PARK7]. The final diagnosis was FTD in the variant of PPA. Four years after the FTD diagnosis, patient 1 died from an ischemic stroke.
Patient 2
A 53-year-old and educated male (13 years), married twice, and employed until the age of 49, had a history of BD type II firstly diagnosed by a trained psychiatrist according to Structured Clinical Interview for DSM-IV-TR [21] from the age of 28, and was treated initially with antidepressants and afterwards with mood stabilizers and antipsychotics. There was no family history of neurological and psychiatric disorders. His first admission to a psychiatric unit was at the age of 43, after attempted suicide for drug ingestion (lamotrigine). Before admission he was treated with lamotrigine 200 mg/day and escitalopram 20 mg/day. After a week of hospitalization in the Psychiatric Unit and stabilization of psychiatric conditions, he was transferred to the Neurodegenerative Disease Unit for further examinations because in the last two years, he presented with progressive dysarthria and ataxia. At neurological examination, progressive impairment in spoken language, anomia, dysgraphia, diffuse plastic hypertonia, and bilateral inexhaustible clonus in the right foot and a limitation of ocular motility in vertical range were found. CSF cytology and chemical-physical characteristics showed a mild increase of proteins (specifically tau and phospho tau levels). MRI showed cortical atrophy in frontal and temporal areas. Furthermore, SPECT imaging showed hypoperfusion in bilateral frontal and temporal areas. The MMSE presented mild impairment (MMSE score: 21.9). Executive functions, verbal memory, and language were the most compromised cognitive domains (Table 1). After genetic assessment, a polymorphism associated with FTD was identified on exon 12 of chromosome 17 (3’UTR+78C/T) [22]. The final diagnosis was FTD with parkinsonism. Only two years after the FTD diagnosis, patient 2 died from community-acquired pneumonia.
DISCUSSION
The severity of behavioral and language changes and the assessment of neurological signs and symptoms in these two patients affected by lifelong BD, raised the suspicion of a neurodegenerative disease, reaching the early diagnosis of FTD before the age of 60 years.
First, at clinical assessment our patients presented with severe decline of specific neurocognitive domains, with relatively preserved memory and visuo-spatial skills in the initial stage, in contrast with other dementias [23]. Several studies suggested the persistence of cognitive dysfunctions as endophenotype in BD patients [11, 24–26]. Regardless of the age, the prominent cognitive deficits in BD appeared to be verbal memory, executive function, and verbal fluency [27, 28]. Dysexecutive syndrome was also considered the core of cognitive and behavioral symptoms in FTD (i.e., attention, organization, abstraction, judgment, problem solving, and mental flexibility) in addition to progressive non-fluent aphasia and dysgraphia [26].
Recent studies demonstrated that patients with BD showed a more severe and accelerated age-related impairment of cognitive functions and language abilities (comprehension, expression, verbal fluency, and abstraction) in comparison to healthy subjects,particularly after the age of 55 years [29–32]. In both patients, language disturbances were detected at the beginning of changing symptoms toward a neurodegenerative disorder and, particularly in patient 2, this sign was initially misidentified as a conversion disorder, because it arose in connection with a daughter’s birth. However, it did not ameliorate with adequate treatment and the patient, given the preservation of other functions in initial stage, tried to express himself with the keyboard of personal computer. Both patients had better insight into language symptoms, which could contribute to their expressing more depressed thoughts.
According to the association between BD and dementia [5, 6], Lebert and colleagues identified a specific type of post-BD dementia with clinical features of FTD [14] and two studies have described a few cases of patients with marked manic symptoms (i.e., euphoria, irritability, lack of inhibition, and decreased need for sleep) for the first time in their life and subsequent diagnosis of FTD [16, 33]. Moreover, FTD patients have a social conduct disorder with inappropriateness, apathy, and passivity, a loss of emotions and empathy and decreased insight, hyperorality or dietary changes, and compulsive acts or stereotyped behaviors are additional common manifestations of early disease [34]. Behavioral disinhibition and hyperorality like craving for sweet foods could also take part of BD symptoms, but in our cases they represented a dramatic change from the subject’s previous eating habits. Furthermore, they showed higher amounts of apathy. Dysfunction of frontal and temporal areas could represent shared pathways for behavioral and cognitive symptoms.
Brain imaging data about our patients were characterized by mild atrophy of frontal and temporal lobes. For patient 1 only, we had a MRI undertaken two years earlier, and at a comparison with the last scan, she showed a more diffuse atrophy of these cerebral lobes, although first neuroimaging findings were not suggestive of a FTD diagnosis. Therefore, it was difficult to separate structural imaging abnormalities due to BD or FTD pathology in both the patients, although a series of imaging studies have revealed that signs of frontal and temporal dysfunction on regional blood flow and loss of gray matter are common in both diseases and correlated with impairment of cognitive function and illness course [17, 35–37]. Therefore, cognitive deficits may be related to structural brain abnormalities, and the changes at the level of the cingulate cortex (atrophy of frontal and temporal lobes) seem to predispose to frontal and temporal circuit dysfunction [38]. Interestingly, specific perfusive patterns in frontal and temporal areas of FTD patients defined at SPECT correlated with specific cognitive and behavioral profile such as “pseudomanic behavior”, “cognitive”, and “pseudodepressed behavior” endophenotypes [39, 40]. Therefore, the reason for the cognitive and behavioral similarities between BD and FTD could be found in a common frontal and temporal lobes neuropathology, or in the intrinsic and extrinsic factors correlated with BD diagnosis, including genetics, early onset and duration of illness, number and severity of affective episodes, and history of substance abuse and medications [27, 41–44].
Regarding related genes, mutations in the GRN gene were the most frequent causes of autosomal dominant FTD. Moreover, a contribution of GRN has also been reported in sporadic FTD, and common genetic polymorphisms in this gene are associated with schizophrenia and BD [24, 45]. Localized in the region 17q21, GRN was previously associated with BD [46]. Furthermore, a neuropathological study in young patients affected by psychiatric disorders including BD antemortem, showed the presence of protein deposits such as Tau or TDP-43 typical of frontotemporal lobar degeneration (FTLD), the general category of pathologic process underlying most cases of FTD [47]. Recently, a hexanucleotide repeat expansion in a non-coding region of the C9ORF72 gene has been identified as the cause of chromosome 9p21-linked FTD [48, 49]. More than 40% of patients with C9ORF72-FTD had a psychiatric disorder [50]. Recently, Meisler and colleagues reported C9ORF72 expansion in a family with BD and FTD, highlighting a possible etiological relationship between the C9ORF72 expansion and disease progression from BD to FTD [51]. In our cases, only patient 2 carried a genetic mutation.
We must acknowledge some limitations of the present case-report study. Firstly, we had no determination of the C9ORF72 expansion [51, 52] and no postmortem neuropathological examinations of both the patients to confirm definitively the diagnosis of FTD, i.e., a histochemical and immunohistochemical diagnosis on autopsy brain of FTLD [53]. Furthermore, several different ways of approaching the question of a relationship between BD and FTD are possible: 1) shared predisposing factors, mainly genetic [52, 54], 2) a causal relationship in which patients with BD are at greater risk for developing FTD, 3) a reverse or mimic relationship in which FTD presents with a bipolar-like syndrome [55], 4) a sporadic co-occurrence of BP and FTD, 5)a late-onset BP preceding the diagnosis of FTD [56], and 6) a specific dementia syndrome arising as a result of bipolarity as described by Lebert [14] but that does not seem to correspond to the criteria of the main types of dementia, including FTD. The third option comes up fairly often in clinical practice, but it is not the focus of the current report. Patient 2 may have been an example of a shared genetic predisposing factor with a polymorphism associated with FTD identified on exon 12 of chromosome 17 (3’UTR+78C/T) [22], but no similar variant found in patient 1. Furthermore, a sporadic co-occurrence of BD and FTD in our patients cannot be excluded. Regarding the second option with a greater clinical impact, only two cases cannot address satisfactorily this issue. Clearly, the generalizability of our findings was constrained, but the usefulness of case-series studies in psychiatric translational research has been recently reported [57]. Our cases could suggest that a long history of BD may increase the risk of developing an early diagnosis of FTD before the age of 60 years, emphasizing the importance for psychiatrists to be aware of the clinical prodromal FTD symptoms. Although BD is principally considered a neurodevelopment disorder, while FTD is a neurodegenerative disorder, follow-up studies of cognitive deficits, imaging, and genetics in BD patients could elucidate the possible correlation between these major diseases and may have implications for pathogenesis, as well as for treatment. Furthermore, whether or not BD patients with common genetic risk variants may be also more prone to develop FTD [58, 59] would be a worthwhile objective for further longitudinal studies.
DISCLOSURE STATEMENT
Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/16-0860).