Frontotemporal Dementia: A Brain Disease That Challenges Definitions of Mental Illness

Every practicing psychiatrist has seen a patient whose presentation resembles Chad’s. Chad consulted me almost 2 decades ago, but I remember him well. It was a few months before his 60th birthday. He was “facing mortality” and thought he might be getting depressed. Chad complained of trouble concentrating and said that simple tasks like balancing his checkbook had become more difficult. His legal work no longer engaged him, and he was spending more time on the Internet.

Chad still enjoyed working in his garden and was busy preparing the flowerbeds for a late-summer celebration of his wedding anniversary. He dearly loved his wife, but he was living with a long-standing conflict. He had “always known” that he was gay, and he had kept this a secret for his entire marriage. Now that he was turning 60, he had regrets. It was in this context that he had discovered gay pornography on the Internet. He told me that he was “becoming addicted to the porn,” and that sometimes he even watched while in his law office.

The changes in Chad seemed psychologically understandable and, yet, I had a nagging feeling that this was not an ordinary depression or “late-in-life crisis.” Chad seemed to be lacking in motivation more than suffering from a depressive mood. I also worried that perhaps his judgment was becoming impaired. In other words, Chad was an almost 60-year-old man who was reflecting on his life, rethinking choices he had made, and feeling mildly depressed; but it was possible that, in addition, Chad had a covert medical condition such as a sleep disorder or perhaps an early dementia.

TABLE. Diagnostic approaches to bvFTD for psychiatrists

Psychiatrists are the most intensively trained in the diagnosis of discrete, well-described medical/neurological conditions that might be masquerading as primary psychiatric disorders.

A medical work-up, including a neurology consultation, found no evidence of dementia. The patient’s symptoms were attributed to depression, and reassurance was recommended.

Chad stopped seeing me after 8 months. He felt somewhat better after talking about his life in psychotherapy and taking an SSRI. But his sexual preoccupations continued, and he planned to seek help from a psychologist who specialized in “sexual addiction.”

Chad’s story does not end well. He was suffering from a disease that would end his life, but it took 2 years of declining functioning before MRI evidence of his disorder became clear. Chad’s wife wrote to tell me that Chad had received a diagnosis of frontotemporal dementia (FTD). I always think of Chad when I learn of new findings about FTD. Much has been discovered about this disorder in the years since I saw him.

 Introduction to frontotemporal dementia

FTD is the second most common cause of dementia (after Alzheimer disease) in the population under age 65.¹ The age of onset is usually between ages 45 and 65 but can range from 30 years to over 80. Prevalence is estimated to be about 15 to 22 per 100,000.²

Chad had the most common subtype of FTD, now called the behavioral variant (bvFTD). Patients with bvFTD frequently present with psychiatric symptoms, often years before other features of the disease emerge.² These individuals may look like they have late-onset major depression, psychosis, bipolar disorder, or OCD. Mental health professionals are very likely to be consulted, either by the patient or by family members. This, in and of itself, makes it important for psychiatrists to be familiar with FTD.

FTD is a brain disorder. But, in masquerading as what psychiatrists call primary psychiatric disorders, FTD challenges us to re-examine how we think about the relationship between “mental illness” and “brain disease.” Indeed, FTD inspires us to expand our knowledge-base and our clinical acumen into realms beyond the usual boundaries of our field.

In this article I will present a summary of what psychiatrists need to know about FTD. I have included summaries of case examples from the literature to convey the wide variety of possible psychiatric presentations of bvFTD.

What is frontotemporal dementia?

In 1892, the Czech psychiatrist Arnold Pick described the first case of what would today be classified as a FTD. The term FTD actually refers to a large class of neurodegenerative disorders that vary in both clinical presentation and underlying pathology, but all of these disorders manifest with cortical degeneration in the frontal and temporal lobes.

FTD has been the subject of intensive research, including efforts to categorize various clinical and neuropathological subtypes. Researchers have found an association between FTD and mutations in a small number of genes (most commonly, C9orf72, MAPT, and GRN). There also are accumulations of protein aggregates (for example, tau or TDP-43) in neural tissue, and it is hypothesized that these may spread from cell to cell in a way that is similar to what occurs in prion disease.² In addition, there is some evidence that functional connectivity patterns may differ in bvFTD and Alzheimer disease.³

With many of the clinical subtypes of FTD, patients and their families are likely to consult with neurologists because the first symptoms are disturbances of language or movement, making it clear that the problem is probably a brain disorder. These types of FTD include primary progressive aphasias, progressive supranuclear palsy, corticobasal syndrome, and FTD with motor neuron disease. (Amyotrophic lateral sclerosis [ALS] is the most common motor neuron disease in adults.)

FTD-behavioral variant. Patients who have the most common type of FTD, the behavioral variant (bvFTD), are much more likely to come to the attention of a psychiatrist because they first present with changes in behavior and personality, impaired executive functioning, and/or symptoms that mimic late-onset primary psychiatric disorders. BvFTD often erodes qualities that are considered to be the very essence of the patient’s temperament, character, identity, and sense of values.

The most common early symptoms of bvFTD include various combinations of the following:

1) Disinhibition manifests as behaviors that are socially inappropriate, impulsive, or careless, or that exhibit poor judgment and lack of consideration of consequences. Poor manners, lack of social decorum, and an absence of any sense of embarrassment are characteristic. Patients may also be irritable, superficially jocular and euphoric, or depressive.

2) Apathy may express itself as inertia, disinterest, social withdrawal, and/or a lack of engagement, drive, or motivation.

3) Lack of empathy may manifest as self-involvement, diminished interpersonal warmth, loss of sympathy for others, and/or lack of regard for the effect of the individual’s behaviors on the feelings of others.

4) Repetitive, stereotyped, or perseverative behaviors may include simple movements or speech patterns or more complex rituals and compulsions.

5) Substantial changes in food preferences and eating habits may involve a shift to over-consumption of sweets and carbohydrates, binge eating, gluttony, and substantial weight gain. Hyperorality eventually may include mouthing of non-food objects.

6) Impairment of executive functions is common, while memory and spatial orientation are relatively preserved.

7) The lack of insight may be profound.

The diagnostic challenge of bvFTD for psychiatrists. The gradual emergence of symptoms in bvFTD can make it difficult, early on, to recognize this disorder as being something other than situational. In addition, when patients and their families believe the problem is psychiatric, this “frames” the problem and may bias the initial diagnostic impression for the clinicians with whom they consult.

Patients with early bvFTD are also a diagnostic challenge because of the substantial overlap between the symptoms of FTD and the symptoms of certain primary psychiatric conditions: disinhibition and hypomania or ADHD; stereotyped/repetitive behaviors and OCD; and also apathy and depression. MDD is the most common psychiatric diagnosis given to patients who eventually receive a diagnosis of bvFTD.²

A case presentation in The New England Journal of Medicine included this testimony from the wife of “A 31-Year-Old Man with Personality Changes and Progressive Neurologic Decline.”⁴ This patient was remarkably young and had an unusually rapid downhill course. The wife succinctly describes characteristic behavioral changes of bvFTD in her husband and, sadly, the number of medical professionals who missed his diagnosis.

During my pregnancy, my gregarious husband became socially withdrawn. His behavior became erratic: he bought things we could not afford, began having trouble meeting deadlines and following the work dress code, and withdrew from his friends. He became obsessed with listening repeatedly to Harry Potter audio books, to the extent that when I was in labor, I had to ask him to put his iPod away.

By the time our child was 6 months old, my husband was functioning so poorly that I did not feel comfortable leaving them alone together. Accompanying him to a routine appointment, I said to his primary care physician, “My husband is acting so weird, does he have a brain tumor?” She was the first of eight medical and mental health professionals who failed to make the diagnosis.⁴

This patient died just after his child turned 4. The cause of his bvFTD was thought to have been a spontaneous mutation in the MAPT gene, one of a small set of genes that have been associated with FTD.⁴

Most cases of FTD are due to mutations that are sporadic (spontaneous).¹ However, in 40% of FTD cases there is a family history of dementia, psychiatric disease, and/or motor neuron disease, and in 10% to 20% of these cases the mutations are autosomal dominant.

Behavioral variant FTD associated with mutations in C9orf72

In 2011, 2 groups of researchers independently identified the most common genetic cause for bvFTD as an expansion mutation (extra hexanucleotide repeats: GGGGCC) on chromosome 9 (C9) of the C9orf72 gene.² This mutation was also found to be probably the most common genetic cause of ALS and the FTD-ALS complex.

Realizing that sound information about the subset of FTD patients who exhibit the C9orf72 mutation would be important for practicing psychiatrists, the American Neuropsychiatric Association (ANPA) Committee on Research reviewed the literature on psychiatric aspects of this mutation and published their report in February 2017.²

The committee found that patients with expansion mutations in the C9orf72 gene may experience psychiatric symptoms for 4 or 5 years before the emergence of the more typical manifestations of bvFTD. In addition, neuroimaging results initially may be negative, and one cannot count on the presence of a family history of dementia; many patients have only a family history of what sound like psychiatric disorders.

The ANPA Committee literature review also elucidated what is currently known about the most common psychiatric presentations of FTD patients with C9orf72 mutations.

The most common psychiatric presentations in FTD patients with C9orf72 mutations. Psychotic symptoms appear to be the most common and may take the form of “various combinations of delusions or overinvested ideas and multimodal hallucinations.”² The delusions may be persecutory, jealous, religious/mystical, or grandiose, and somatic preoccupations are common. Generally, in the published literature, the patients’ psychotic symptoms were not responsive to antipsychotic medications.

Less often, onset of bipolar disorder with mania after the age of 40 was the manifestation of C9orf72 mutations. The small number of patients with late-onset bipolar disorder with mania who were reported in the literature tended to respond to treatment with lithium. In addition, patients with C9orf72 expansion mutations may present with other mood disturbances, including “depressive episodes with or without catatonia, dysphoria with suicidal thoughts or attempts, and depression-related cognitive disturbances (‘pseudodementia’).”²

Late-onset OCD has been described as part of the prodrome of C9orf72 mutations, but OCD-like symptoms are commonly seen as part of the presenting picture in bvFTD even in patients who do not have this specific mutation.

Case examples of patients with C9orf72 mutations

As part of their longitudinal studies on aging and neurodegenerative disease, the University of California, San Francisco Memory and Aging Center found that some of their patients had expansion mutations in C9orf72. This gave them an opportunity to prospectively follow individuals who carried this mutation and to “characterize psychiatric symptomatology during the earliest phases of the illness.”⁵ In 2015, they published a paper that included 3 of these patients, summarized below.

FTD developed in each of these 3 patients; however, given that these are single case examples, one cannot assume a simple causal relationship between the C9orf72 gene mutation and the patient’s psychiatric symptoms. These case examples demonstrate how the diagnosis of neuropsychiatric disorders is a dynamic process that unfolds over time and that it is important to include FTD in the differential when encountering these kinds of presentations.

Late-onset psychosis and a C9orf72 mutation. Mr. M first began to have delusions and auditory hallucinations at age 58. He heard “voices from other continents that spoke to him through his hearing aid and eyeglasses.” He would cover mirrors to keep from being observed and hide in the closet to elude the Mafia. He also began to think that he was a “sex god,” and he went into his neighbors’ homes with the idea that they were interested in having sex with him. These delusions and hallucinations lessened over 2 years, giving way to apathy and a voracious appetite; often he would eat whatever was in front of him, food as well as non-food objects.

Late-onset bipolar disorder and a C9orf72 mutation. Ms. G had a first manic episode at age 53. Her symptoms included rapid thought, grandiose notions such as intentions to start a new religion, poor sleep, and then over-familiarity with strangers. She was hospitalized and responded to treatment with lithium. Diagnosed with bipolar disorder, she was stable on valproic acid until age 63. At this point her husband felt that her cognition was below her baseline, and she was seen at the Memory and Aging Center. There, she was found to have very mild executive dysfunction and verbal memory impairment; she received a diagnosis of mild cognitive impairment. Two years later, her affect had become strange and she became disinhibited. By age 68 she had ALS and was wheelchair-bound.

Late-onset OCD and a C9orf72 mutation. At age 60, Ms. A began to display rigid, obsessive-compulsive behaviors, including checking email compulsively and obsessively organizing household items. A community physician diagnosed OCD. Then, over the next 2 years, she became increasingly apathetic and withdrawn. Her judgment deteriorated, her empathy diminished, and she became disinhibited. Some of her behaviors included personal postings on an Internet sex site, losing money in an on-line scam, and making inappropriate remarks in public.

Pointers for psychiatrists in evaluating patients who might have bvFTD

With current information about bvFTD, how might one approach the psychiatric evaluation of a patient like Chad? The Table provides some important points to help the psychiatrist when evaluating patients with suspected bvFTD.

Conclusion

Early identification of bvFTD allows patients to have time to put their affairs in order and to participate in planning for their own future care. In addition, an accurate diagnosis is extremely helpful to family members who often are befuddled by the changes in their loved ones’ behaviors and who also may be facing extremely difficult social, financial, and/or legal predicaments.

Among mental health professionals, psychiatrists are the most intensively trained in the diagnosis of discrete, well-described medical/neurological conditions that might be masquerading as primary psychiatric disorders. When it comes to bvFTD, psychiatrists have an especially important role in the early identification of patients who may have this disorder.

Disclosures:

Dr. Schildkrout is Assistant Professor of Psychiatry, Part-time, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA. She is the author of 2 books, Unmasking Psychological Symptoms: How Therapists Can Learn to Recognize the Psychological Presentation of Medical Disorders and Masquerading Symptoms: Uncovering Physical Illnesses That Present as Psychological Problems.

References:

1. Olney NT, Spina S, Miller BL. Frontotemporal dementia. Neurol Clin. 2017;35:339-374.

2. Ducharme S, Bajestan S, Dickerson BC, Voon V. Psychiatric presentations of C9orf72 mutation: what are the diagnostic implications for clinicians?J Neuropsychiatry Clin Neurosci. 2017;29:195-205.

3. Zhou J, Seeley WW. Network dysfunction in Alzheimer’s disease and frontotemporal dementia: implications for psychiatry. Biol Psychiatry. 2014; 75:565-573.

4. Miller BL, Dickerson BC, Lucente DE, et al. Case 9-2015: a 31-year-old man with personality changes and progressive neurologic decline. N Engl J Med. 2015;372:1151-1162.

5. Block NR, Sharon JS, Karydas AM, et al. Frontotemporal dementia and psychiatric illness: emerging clinical and biological links in gene carriers. Am J Geriatr Psychiatry. 2016;24:107-116.