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. Author manuscript; available in PMC: 2021 Apr 1.
Published in final edited form as: J Neuropsychiatry Clin Neurosci. 2020 Jun 5;32(4):376–384. doi: 10.1176/appi.neuropsych.20010003

BIPOLAR DISORDER AMONG PATIENTS DIAGNOSED WITH FRONTOTEMPORAL DEMENTIA

Mario F Mendez 1,2,3, Leila Parand 1,3, Golnoush Akhlaghipour 1
PMCID: PMC7606722  NIHMSID: NIHMS1624694  PMID: 32498603

Abstract

Background:

Investigations have documented manic/hypomanic symptoms from bvFTD, suggesting a relationship of BD with bvFTD.

Objective:

To determine the relationship of bipolar disorder (BD) among patients with behavioral variant frontotemporal dementia (bvFTD).

Methods:

In addition to a literature review, we reviewed the psychiatric histories of 137 patients with bvFTD and identified those with a prior diagnosis of BD. This study evaluated the clinical characteristics of their BD diagnosis, their family histories, features of their bvFTD, the results from fluorodeoxyglucose positron emission tomography (FDG-PET), and autopsy findings.

Results:

Among the 137 patients, 14 (10.2%) had a psychiatric diagnosis of BD of whom 8 met criteria for BD (6 Type I; 2 Type II) 6–12 years preceding onset of classic symptoms of progressive bvFTD. Seven of these had a family history of mood disorders, four had bitemporal predominant hypometabolism on FDG-PET, and two had a tauopathy involving temporal lobes on autopsy. Three additional patients with late-onset BD I proved to have a non-progressive disorder mimicking bvFTD. The remaining three patients with bvFTD had prior psychiatric symptoms that did not meet criteria for a diagnosis of BD. The literature and one of our patients further suggested a shared genetic mutation in a few patients.

Conclusions:

Manic/hypomanic episodes years before other symptoms of bvFTD may be a prodrome of this dementia, possibly indicating anterior temporal-involvement in bvFTD. Other patients with late-onset BD prove to have the non-progressive FTD phenocopy syndrome. Finally, rare bvFTD patients have a genetic predisposition for both disorders.

Keywords: Frontotemporal dementia, mania, bipolar disorder

INTRODUCTION

Behavioral variant frontotemporal dementia (bvFTD) is a progressive neurodegeneration of the frontal and anterior temporal lobes that usually presents in mid-life with alterations in personality and emotional regulation {1, 2}. BvFTD, the second most common dementia among patients <65 years {3}, includes a progressive decline in executive and other cognitive abilities, as well as behavioral changes {4}. The earliest personality and emotional features tend to be apathy or abulia, disinhibition or impulsivity, and loss of sympathy or empathy {2}, but a wide range of behavioral symptoms can occur including manic-like behavior and symptoms {5, 6}. Many, if not most, patients with bvFTD present to psychiatrists who have to distinguish early bvFTD from primary psychiatric disorders {7}.

Some patients with bvFTD can look similar to bipolar disorder (BD) on initial presentation {8–10}. Patients with bvFTD can manifest with euphoria or emotional outbursts, talkative or pressured speech, racing thoughts, task-oriented behavior, increased energy and psychomotor activity as well as irritability, distractability and disinhibition {6, 8, 11}. Conversely, the manifestations of BD include, not only manic hypomanic, or depressive episodes {12, 13}, but also neurocognitive impairments in complex attention, executive functions, and other changes similar to bvFTD {4, 14–16}.

This overlap in symptoms of BD and bvFTD suggests possible shared origins and mechanisms between these two disorders and raises the question of whether BD precedes or leads to bvFTD {17}. Indeed, a number of investigators have reported a link between the two disorders {18, 19}; yet, the exact association is unclear. We hypothesize that, beyond shared presenting symptoms, manic or hypomanic episodes can be a prodrome of bvFTD in some patients, and late-onset BD can present as a bvFTD mimic, or “FTD phenocopy”, in others {20, 21}. Accordingly, we reviewed our clinical base of well-diagnosed patients referred for bvFTD who also had a psychiatric diagnosis of BD and reviewed the literature on the association between these two disorders.

METHODS

Participants

The participants in this study presented for evaluation to a university clinic specialized in bvFTD. All of these patients had neurobehavioral changes suggestive of bvFTD and underwent a comprehensive evaluation, laboratory assessment, and magnetic resonance imaging (MRI); most had fluorodeoxy-glucose positron emission tomography (PET) of the brain. A total of 137 patients met initial clinical criteria for bvFTD (Possible, Probable, or Definite) for this review {2}. The patients diagnosed with bvFTD had to a have a knowledgeable informant and an initial history of progressive deterioration of behavior and/or cognition from their prior “normal” baseline level or behavior. Changes included three of the following: apathy, disinhibition, loss of empathy, repetitive behaviors, dietary changes, and a predominant dysexecutive cognitive profile {2}. Patients met criteria for Possible bvFTD, unless neuroimaging showed frontal and/or anterior temporal changes supportive of a diagnosis of Probable bvFTD or there was Definite bvFTD on neuropathology. Among these 137 bvFTD patients, we further identified all those that had a prior diagnosis of BD made by a psychiatrist. The participants for this study were part of an institutional review board approval for this research.

Procedures

For the subgroup with a prior psychiatric diagnosis of BD, we abstracted historical evidence of the prior psychiatric symptoms that lead to their BD diagnosis, focusing on mania, hypomania, or a history of elevated, expansive, or irritable mood {22}. This review evaluated criteria for manic or hypomanic episodes including three of the following: inflated self-esteem or grandiosity, decreased need for sleep, more talkative than usual or pressure to keep talking, flight of ideas or subjective experience that thoughts are racing, distractability, increase in goal-directed activity or psychomotor agitation, and excessive involvement in activities that have a high potential for painful consequences. We also assayed criteria for depression or depressive episodes and family history suspicious for mood disorders.

RESULTS

Among the 137 patients, 14 (10.2%) had a preceding psychiatric history reported to be indicative of a bipolar spectrum disorder. On review, 3 of these patients did not meet criteria for BD but had had other psychiatric symptoms that lead to their BD diagnosis, including suicidal behavior, paranoia, impulsivity, antisocial behavior, and obsessive-compulsive behavior. The remaining 11 patients fell into two categories:

“Prodromal Group”

Eight (6 males, 2 females) had a clear prior history of mania (6 with BD I) or hypomania (2 with BD II) occurring 6–12 years prior to an established diagnosis of progressive bvFTD (See Table 1). The mean age of onset of mania/hypomania (48.25±13.0) preceded the mean age of onset of bvFTD (57.25±11.9) by an average of 9 years. In one patient, we could not verify the past psychiatric and family histories because of his immigrant status and loss of family members to war. The other seven had a positive family psychiatric history, usually of depression, and one had a chromosome 9 open reading frame 72 (C9orf72) mutation. Of these eight patients, four had prominent bitemporal hypometabolism with or without frontal involvement on FDG-PET and another had less prominent temporal lobe hypometabolism. Most of the changes were bilateral at the time of imaging, and no clear laterality difference was discerned. Both patients with autopsies showed FTD changes with tau positive intranuclear inclusions involving frontal and temporal neocortex in one and inferior temporal lobes in the other.

Table 1:

Behavioral variant Frontotemporal Dementia (bvFTD) Patients with Bipolar Disorder (BD)

Patient Mania/Hypomania Psychiatric Onset Age bvFTD Criteria bvFTD Onset Age Family History (1° relatives) FDG-PET imaging
1 (F) No-sui, paranoia 25 Yes-Probable 34 Yes-dep, sui RF,BT
2 (F) Yes-mania+psych; dep 37-dep 40-mania Yes-Probable 48 Yes-sui BF (left (worse)
3 (M) No-sui, impulsive 58 Yes-Probable 58 Unknown BT
4 (M) Yes-treated dep→ persistent mania 33 (cyclothymia 20’s) Yes-DefiniteA 45 Yes-dep, sui BF
5 (M) Yes-hypomania,dep 42 Yes-Possible 48 Yes-dep unavailable
6 (M) Yes-mania and dep (ECT at 56) Yes-Probable 68 ??-lost in war BT>BF
7 (M) Yes-mania+psych 61 No 61 No Mild P
8 (M) Yes-mania+psych, q4–6 month cycles 63 Yes-Probable 70 Yes-dep, C9orf72 BT
9 (M) Yes-mania+psych 34 Yes-Probable 44 Yes-dep BF,BT
10 (M) No-antisocial, OCD 31 Yes-Probable 57 Yes-dep BT
11 (F) Yes-hypomania,dep 59(approx) Yes-Probable 69 Yes-dep, BD BT
12 (M) Yes-mania+psych 62 Yes-DefiniteB 66 Yes-dep BT>BF
13 (M) Yes-severe mania 60 No 60 No Mild TP
14 (F) Yes-mania+psych 55 No 59 No Normal
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BT,BF=bilateral temporal or frontal; C9orf72=chromosome 9 open reading frame 72; Dep=depression; OCD=obsessive-compulsive dis.; P,PT=parietal,parietotemporal; Psych=psychotic; Sui=suicidal.

A

Autopsy: severe FTD changes (especially right frontal) with tau-positive inclusions in frontal and temporal neocortex, plus subcortical leukoencephalopathy/hyalinizing arteriopathy (Binswanger’s) of arterioles.

B

Autopsy: superficial spongiosis and other FTD changes; tau positive inclusions in inferior temporal lobes.

“Phenotype Group”

Three additional patients (2 males, 1 female) did not meet criteria for progressive bvFTD in that they lacked frontotemporal changes on FDG-PET and did not manifest clinical worsening of FTD behaviors or neurocognitive measures when followed for 3–7 years. The mean age of onset of manic episodes (58.87±3.21) preceded the mean age of onset of bvFTD (60.0±1.0) by about a year.

Additional Observations

Other characteristics of the mania and hypomania patients and symptoms were obtained. All the patients with manic episodes underwent psychiatric hospitalization, most with psychotic features. All were on various antipsychotic medications except two, and only one was on lithium. Depressive episodes were present in six patients with subsequent progressive bvFTD, but not in the three non-progressive patients, all three of whom had severe, recurrent manic episodes with hospitalizations. Only one patient approached being a rapid cycler (patient #8) and another was reported by relatives to be cyclothymic during his college years (patient #4). This same patient had his initial and persistent manic episode precipitated by antidepressant medication, but there was no other evidence of substance/drug induced mania. Otherwise, all manic and hypomanic episodes were of relatively late-onset with the possible exception of the one patient whose psychiatric history could not be verified (patient #6) and the one whose family suggested that he could have been cyclothymic during his college years.

DISCUSSION

We found a heterogeneous relationship of BD with bvFTD. The symptoms of mania or hypomania and bvFTD overlap, and there are a number of reports of manic behavior as an initial manifestation of bvFTD {7, 9–11, 23–25}. Given this overlap of symptoms, we examined patients in a bvFTD cohort and found that 10% carried a prior diagnosis of BD, far greater than the proposed wordwide prevalence for bipolar spectrum disorders of 2.4% {26}. On further analysis of their psychiatric histories, only 11 (8%) met criteria for BD and among these, three were non-progressive “bvFTD phenocopies” {20, 21}. The results suggest that late-onset BD can be both a prodrome of bvFTD or lead to cognitive/behavioral changes that mimic bvFTD.

Investigators have established manic or manic-like symptoms as potential presentating features of bvFTD {6, 9, 11, 27}. There are reports of manic behaviors specifically with bilateral (right>left) temporal lobe degeneration in bvFTD even with relative sparing of the frontal lobes {6, 28–30}. Other reports describe secondary mania from strokes and neurological lesions involving the right inferolateral frontal and basotemporal regions {29, 31, 32}. Hence, manic symptoms and bvFTD may share a common neuroanatomical dysfunction, pointing to a potential link between BD and this dementia {33, 34}.

BD may be a prodrome to bvFTD. Among the major psychiatric syndromes, BD is most frequently associated with dementia {35}, and among major dementias, bvFTD is most commonly preceded by psychiatric symptoms {7}. Although, recent meta-analysis of longitudinal (1–9 year) studies failed to find significant differences in rates of cognitive decline between BD patients and controls {36}, many others studies from around the world have reported an increased risk of dementia among cohorts of patients with BD, particularly those with BD I {37, 38}, compared to controls, with hazard ratios ranging from 2.36–7.52 {37, 39–44}. Their dementia syndrome may be more like bvFTD than other dementias such as Alzheimer’s disease {45}. One large epidemiological study of over a thousand FTD patients reports a background of mood disorders in 19%, many with BD {46}, and, compared to other major types of dementia, patients with bvFTD are over twice as likely to have a diagnosis of BD {7}. Although patients with lifelong BD may evolve to FTD {18}, it is late-onset BD that has the most significant risk for developing bvFTD {39, 43}. Most of our patients, and others from the literature, show a prodromal relationship of several years between episodes of mania and the development of clinical and FDG-PET evidence of bvFTD {8}. These studies and our patients indicate that relatively late-onset BD can precede typical progressive bvFTD.

Other reports of late-onset BD describe the emergence of a non-progressive bvFTD mimic {10, 47, 48}. This is consistent with the bvFTD phenocopy syndrome, which lacks the neuropathology of FTD in most autopsied cases {20, 21}. This is also consistent with three of our patients and others with BD I who have developed bvFTD-like symptoms without progression or neuroimaging changes over subsequent years of follow-up {47}. For example, Vorspan et al, 2012 describe a 54 year old BD patient with relapsing-remitting, agitated manic episodes and symptoms of bvFTD followed for 7 years without progression {25}. Severe or numerous manic and depressive episodes could result in frontally predominant cognitive and behavioral injury and an eventual non-progressive dementia mimic of bvFTD {10, 30, 35, 41, 42, 49, 50}. Episodes of mania and depression close in time to the dementia, as in our three non-progressive patients, may leave a “bvFTD” in their wake, even when euthymic. Patients with BD may have relatively stable cognitive changes in executive functions (working memory and cognitive control or cognitive flexibility and response inhibition), and verbal memory {4, 51–53}, and most routine executive function tests may fail to distinguish the cognitive changes of BD from bvFTD {54, 55}. The etiology of cognitive changes from manic or depressive episodes could be due to an accelerated aging in cognitive control processes {40, 56–58}, prefrontal structural or functional abnormalities {59–62}, injury from neuroinflammatory activity or oxidative stress {63, 64}, frontal lobe and posterior white matter abnormalities {65–67}, or alterations in connectivity, networks or interoceptive circuits {64, 68}.

A third, but apparently rare, association of BD with bvFTD is through a common genetic predisposition. Among patients with familial bvFTD, psychiatric symptoms are the initial manifestations of up to half of those with the chromosome 9 open reading framing 72 (C9orf72) mutation, a nucleotide repeat disorder, and one quarter of those with a progranulin (GRN) mutation, with decreased progranulin levels {1, 69}. Some have found a background of BD and subsequent bvFTD with C9orf72 {70, 71}, as in one of our patients, and with GRN mutations {19, 72}. Investigators have considered an expanding number of C9orf72 nucleotide repeats in familial BD and psychosis leading to bvFTD {48, 70, 72, 73}, but others have failed to find a link to BD among relatives of C9orf72 patients or a clear relationship with the number of repeats {74, 75}. There is no reported association with BD in microtubular-associated protein tau (MAPT) mutations {76}, the third common genetic form of bvFTD. For C9orf72 and GRN mutations, the literature raises the hypothesis that the close link between BD and bvFTD may have a genetic predisposition but in relation to other factors, either environmental or additional genetic, such as variants of the glycogen synthase kinase 3β gene {77}.

There are important limitations to this report. First of all, it is a retrospective review albeit of carefully evaluated patients referred to a program specializing in bvFTD. Nevertheless, the report is clinical, observational, and descriptive. Hence, there are a number of potential confounding factors to consider, such as selection bias on referral to a specialty clinic. As in any retrospective study where information is historical, it is subject to questions of reliability and completeness, which may be particularly a factor for psychiatric and behavioral symptoms. Wherever possible, we compared the secondary reports with hospitalization records available for many of the manic episodes. Another factor is the disproportionate number of males evident in this sample and present across the different subgroups. Finally, the imaging results of necessity including imaging reports from other institutions and facilities where direct analysis of brain scans was not available.

In conclusion, the relationship of BD with bvFTD is heterogeneous. Manic or hypomanic episodes may indicate a prodrome heralding bvFTD, possibly with early right>left temporal involvement. Late-onset BD may also present as a bvFTD mimic, or bvFTD phenocopy which is often mild, non-progressive, and without further cognitive decline or definitive neuroimaging or neuropathological changes. Much less frequentlys, there appears to be an association of BD with a shared genetic predisposition from mutations in the C9orf72, GRN, or other genes. These are preliminary conclusions, but they can lead to more research on the concepts of a late-onset BP prodrome of bvFTD and late-onset BP leaving a non-progressive bvFTD phenotypic profile.

Table 2:

Studies assessing Bipolar Disorder (BP) and behavio ral variant frontotemporal dementia (bvFTD)

Reference Objective Patients and Methods Results Conclusions
Cerami et al, 2011{72} FTD with GRN mutation and preceding BPD symptoms Two patients (2M, age 57–60s) with GRN mutation Both patients had years of preceding emotional dysregulation or dysphoric hypomania and depressive episode appearing in midlife Possible BP prodrome phase preceding FTD
Dols et al., 2016 {47} BPD patients with late-life bvFTD mimic Case report: A bvFTD-like syndrome in 4 patients (4M; ages 6278) with longstanding BD Diagnosis of BD I for ≥10 years; Late apathy, disinhibition, loss of empathy and insight, repetitive behaviors, mild executive dysfunction; Non-progressive for 3–7 years; Normal imaging, non-diagnostic CSF and negative C90rf72 Non-progressive bvFTD mimic in some patients with longstanding BD
Floris et al, 2013 {71} Longstanding BD preceding bvFTD with a C9ORF72 mutation Case Report: Recurrent manic symptoms (M, 42), BD Type I, and subsequent bvFTD with C9ORF72 mutation The patient developed bvFTD 22 years (age 64) after initially presenting with BPD I. He proved to have repeat expansions of C9orf72 (>70 repeats). C9ORF72 is associated with phenotypic variability that may include BD
Ibanez, 2012 {8} Atypical presentation of bvFTD Case report A 44-year-old man with diagnosis of FTD by brain imaging with several years of preceeding bipolar symptoms with psychosis BD as potential prodrome of bvFTD
Kerstein et al, 2013 {9} bvFTD mimicking BD Case report A 65-year-old patient with close diagnostic criteria for BD and FTD bvFTD can present as BD
Lai et al, 2018 {46} To compare psychiatric disorders across dementia subtypes Aggregated two national databases and estimated 2-year prevalence of mental health disorders across five dementia subtypes, including 1,181 patients with bvFTD. About 25% of patients had at least one mental health disorder, with 2-year prevalence reaching 30%–45% in FTD. Compared with other subtypes, patients with FTD had the highest prevalence of mood (19%), anxiety (20%), and substance use (19%) disorders, as well as suicidal behavior (4%). Mental health disorders, especially mood disorders, are common among patients with bvFTD.
Lebert et al, 2008 {50} To characterize the dementia in patients with BD 13 (9F/4M) BD patients: Mean age 70.8 (7.7); Dementia with 6.1 (2.8) years follow-up None met criteria for bvFTD; Common executive dysfunction and frontal behavioral syndrome; Moderate EPS in 10; Functional imaging (10) showed decreased frontotemporal uptake There may be a specific post-bipolar dementia that looks like bvFTD in several respects
Masouy et al, 2011 {49} To propose a potential link between BD and dementia Two patients (M, 62 and F, 77) each with about 30 years of BD I and late life deterioration Late cognitive deterioration during euthymic phase with deficits in attention, verbal memory, executive functions, and behavior plus cerebral abnormalities on imaging A “specific dementia” in BD with similarities to FTD but with only mild worsening
Meisler et al, 2013 {70} C9orf72 mutation in patients with BD 89 patients with BD screened for C9orf72 One male BD patient (1%) had C9orf72 expansion (1420 kilobases) inherited from parent (8.5–20 kilobases) with BD who progressed to bvFTD C9orf72 may be associated with a form of BPD that progresses to FTD
Monji et al, 2014 {78} Late-onset BD with behavior and imaging similar to bvFTD Case report This study reported a patient with BD misdiagnosed as bvFTD, due to abnormal behaviors and neuroimaging observations BD can present like bvFTD
Papazacharias et al, 2017 {18} 2 patients with lifelong BPD develop FTD in later life A 56 year old woman with BD I and a 53 year old man with BD II developed signs and symptoms of FTD spectrum disorders Examination showed declines of cognitive functions, behavioral, and neurological signs consistent with FTD spectrum, and MRI and functional imaging changes in frontal and temporal areas. Lifelong BD may increased the risk for developing FTD before age 60
Pavlovic et al, 2011{48} Lifetime BD witl late life bvFTD Case report: 68 year old woman with 35 year history of BPD I developed bvFTD Patient met criteria for bvFTD and had a progressive deterioration with frontal atrophy on CT and MRI, frontal-temporal hypoperfusion on SPECT BD may represent a preclinical phase preceding the onset of FTD
Rubino et al, 2017 {19} Late onset BD evolving into bvFTD in patient with GRN mutation Case report: Late-onset BD (M, 54) developing bvFTD (age 68) with GRN mutation Initial manic symptoms at age 54 progressed to BD at 55 followed by deterioration with apathy at 68 and marked PET frontotemporal hypometabolism. He had a mutation in the GRN gene Late-onset BD that developed into bvFTD over time, carrying a mutation in the GRN gene
Vorspan et al, 2012 {25} Association of manic episodes with bvFTD-like clinical changes A 54 year old woman with BD I was diagnosed with bvFTD during a manic episode but had neurocognitive improvement afterwards Each subsequent relapse was associated with cognitive deficits which subsided afterwards despite continued frontal hypoperfusion Manic episodes may bring out the clinical features of bvFTD
Woolley, et al, 2011 {7} Rates for psychiatric diagnoses in patients with early neurodegenerative disease Comparing rates of psychiatric diagnoses (within 10 years) among patients with bvFTD (n=69), Alzheimer’s disease, semantic dementia, and others The bvFTD patients had the most psychiatric diagnoses (50.7%) with 8 (11.6%) having a BD diagnosis. Young age, education, and a family psychiatric history increased this rate bvFTD is at high risk of being correctly or incorrectly diagnosed with a prior psychiatric disease
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Acknowledgements:

This work was supported by NIH grants #R01AG034499-05 and #1RF1AG050967-01A1

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