Alyssa Caplan, Elana Cohn, Alison Dallich

Sackler School of Medicine, Tel Aviv University, Tel Aviv

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Introduction

Frontotemporal dementias (FTD) are a group of neurodegenerative diseases defined by progressive changes in personality and social behavior and, in some variants, a decline in speech, marked by visible atrophy of the frontal and/or temporal lobes on MRI. FTD is one of the more common causes of early-onset dementia, with a similar incidence to Alzheimer’s in adults ages 45-64.  The average age of symptom onset is in the late fifties, and it is rarely diagnosed before 40 or after 75 years of age (1).  FTD syndromes share the following core diagnostic features characterized by the Neary Criteria: insidious onset and gradual progression, early decline in social interpersonal conduct, early impairment in regulation of personal conduct, early emotional blunting and early loss of insight (2). 

FTD can be classified into three classic forms: behavioral variant, semantic variant, and progressive non-fluent aphasia. This article aims to further elucidate the three classic presentations of FTD through a series of case studies. These subjects were seen at the University of California San Francisco, Memory and Aging Center, given a clinical diagnosis of FTD and enrolled in a large research study. As part of this study, they underwent a neurological exam with a neurologist and a neuropsychological assessment with a trained neuropsychologist. MRI images were acquired on a 1.5-T Siemens Magnetom VISION system. 

Case Study 1: Behavioral Variant FTD

Mr. X, a previously healthy, right-handed 66-year-old man, presents to the clinic due to progressive changes in behavior and personality. At baseline, he is described by his wife as “reliable, quiet, dignified and intelligent.” His family first became concerned when he began to develop an uncharacteristic ease for speaking to strangers, often initiating conversations and providing unsolicited advice. Shortly after, he began making inappropriate comments in public, loudly calling people “fat” or “hairy.”  His inappropriate comments were exacerbated in structured and ritualized situations, such as telling a TSA agent that he would “shoot them” while going through security at the airport. From a quiet baseline, he had become loud and impulsive. He was also noted to have a severe decline in empathy, no longer showing any concern for what his wife was saying. Mr. X’s diet changed dramatically, including eating large quantities of sweets and adding syrup to all desserts. On neurological testing he was noted by the examiner to be impulsive, apathetic, stimulus bound, and distractible. He required frequent prompting throughout. His MRI showed severe atrophy (R>L) of the frontal and temporal lobes, including ventral and dorsal regions of the pre-frontal cortex, confirming his diagnosis and explaining his significant behavioral and personality changes (Figure 1).

The most common form of FTD is the behavioral variant (bvFTD). Patients with bvFTD show a significant and persistent change in their personality and behavior from their pre-disease state (3).  They may become socially uninhibited and apathetic and may be unaware of their changed behavior and the distress it may be causing their family members (4). They also may develop hyperorality (consuming excessive amounts of food too quickly) as well as compulsive behaviors that cause a very rigid personality state (5). A meta-analysis of imaging studies found that frontomedian networks, which mediate impulse and behavioral control, are most affected in bvFTD along with the right anterior insula and medial thalamus, which regulate emotional awareness (6). 

Case Study 2:  Semantic Variant

Mrs. Y is a 69-year-old, right-handed former teacher who presents to the clinic due to changes in language and behavior. At baseline, Mrs. Y was described as “intense” and “demanding.”  Currently, Mrs. Y exhibits severe difficulties with language with some inappropriate behavior. Her language has declined severely. She uses the term “icepops” as a substitute for many words. When she speaks, she says only a few phrases that are not always appropriate to the situation.  She can still comprehend some commands, but even when told simple things like “go to desk,” she will not know what a desk is. On cognitive testing she scored 0/15 on the Boston Naming Test, a test where participants are shown pictures of items and asked to name them. Her husband describes that she will want to grab strangers’ hands and kiss them.  She is also described as acting “childlike” and will frequently tap her foot impatiently. Her MRI shows significant atrophy in the bilateral temporal lobes with anterior and lateral portions more affected than medial portions, and left greater than right, which helps to explain her language manifestations. There is also mild medial ventral frontal and parietal atrophy seen (Figure 2).

Semantic variant FTD differs from bvFTD in that its core features are not based in behavioral changes but in language loss, specifically impaired single word comprehension while maintaining fluency.  Early on, word-finding difficulty is limited to low frequency items, words and objects they don’t use regularly (7). As the disease progresses, the difficulty assigning meaning to words becomes more pervasive, and they lose both the ability to recall everyday words as well as the concept behind the word.  In patients where the right temporal lobe is more affected, remembering faces of friends and familiar people is more troublesome (1). Similar to bvFTD, these patients have significant difficulty understanding the emotions of others and lose empathy early on in their disease (8). MRI reveals bilateral atrophy of the anterior temporal lobes responsive for semantic processing, with the left more affected than the right, as the left cortex is more greatly involved with language than the right. The atrophy spreads to the posterior temporal and/or inferior frontal lobes as the disease progresses, which is significant due to its integral role in language comprehension (9). 

Case Study 3: Progressive Non-Fluent Aphasia

Mrs. Z is a 72-year-old woman who presents to the clinic because of concerns related to progressive language issues. She first noticed language changes four years earlier when she began to have difficulty pronouncing words and getting words out, although her family did not notice these changes. A year later, her family began to notice language changes including problems with word finding and pronunciation. Currently, Mrs. Z’s speech is slow and intensely effortful. She is deliberate in pronouncing each syllable, often breaking up words into component syllables. She has many distortions in her speech such as “wroot” for “wrote.” Her speech is agrammatic, dropping pronouns and verbs at times.  She also has some difficulty understanding people, especially when they speak in longer sentences. Other than language issues, she and her husband note no additional changes. She is still good at organizing and planning, shops for all of the groceries and takes care of her home, and volunteers a few days a week.  On cognitive testing, she named 15/15 items correctly on the Boston Naming Test. Her MRI showed prominent posterior and dorsal atrophy with widened left sylvan fissure, bilateral supplemental motor area (SMA) atrophy, and anterior thinning of the corpus callosum (Figure 3).  The left sylvian fissure contains the major areas for language comprehension, recall, and articulation, which helps to interpret her clinical presentation.

The distinguishing feature of the final variant, progressive non-fluent aphasia, is articulatory difficulty with effortful, halting speech, and numerous linguistic errors (10). In contrast to the semantic variant, these patients typically retain their single word comprehension but have difficulty understanding long sentences, particularly those with complex sentence structure (11).  In the non-fluent variant, deficits may be restricted to language function for several years before progressing to a more widespread dementia (12). An imaging-supported diagnosis will include atrophy of the left posterior frontal-insular region on MRI, specifically responsible for language articulation (8). 

It is important to keep FTD on the differential diagnosis when examining patients with behavioral or language changes as they are often mistaken for psychiatric conditions or other forms of dementia. As with other types of dementia, over time each variant of FTD progresses to affect overlapping areas of the brain and eventually progresses to an inability to communicate and independently complete activities of daily living.

Current Research in FTD

Current research in the field of dementia is investigating the genetics of these diseases as well as the molecular pathology and various biomarkers, so as to hopefully develop targeted treatments. For example, a clinical trial at the University of California San Francisco is using a histone deacetalase inhibitor to treat FTD patients with a specific gene mutation (13).   

Symptom management is the main goal of most clinical trials. A phase two clinical trial actively recruiting bvFTD patients is looking at the effects of intranasal oxytocin on neural activity and emotion, hoping to target the loss of emotion and empathy (14). A 2015 case study presents a bvFTD patient showing reduced negative behavior symptoms and an improvement in motor symptoms and activities of daily living following four months of treatment with methylene blue (15). A phase two study not yet recruiting would test low-dose lithium, used to treat symptoms of bipolar disorder, to decrease behavioral symptoms, while potentially inhibiting a protein involved with FTD (16). While there is currently no definitive treatment for FTD, there are many promising and exciting therapies in development and in various clinical trial stages.   

Acknowledgements  

The authors would like to thank the UCSF Memory and Aging Center for their guidance and mentorship, access to images and data, and their continued hard work and dedication to Frontotemporal Dementia research.

References

1. UCSF. Frontotemporal Dementia (FTD): Semantic Dementia.  University of California SanFrancisco,n.d. Web 04 April. <http://memory.ucsf.edu/ftd/overview/ftd/forms/multiple/sd>. 
2. Mohandas E,Rajmohan V. Frontotemporal dementia: an updated overview. Indian J Psychiatry. 2009;51:65–69. 
3. Johnson JK, Diehl J, Mendez MF, et al. Frontotemporal Lobar Degeneration: Demographic Characteristics of 353 Patients. ArchNeurol2005; 62:925. 
4. Williamson C,AlcantarO, Rothlind J, et al. Standardized Measurement of Self- Awareness Deficits in FTD and AD. J Neurol Neurosurg Psychiatry 2010; 81:140. 
5. Rascovsky, Katya et al. “Sensitivity of Revised Diagnostic Criteria for theBehavioural Variant of Frontotemporal Dementia.” Brain 134.9 (2011): 2456–2477. PMC. Web. 21 Aug. 2017. 
6. SchroeterML, Raczka K, Neumann J, von Cramon DY. Neural networks in frontotemporal dementia—a meta-analysis. Neurobiology of Aging 2008; 29:418-426. 
7. Mesulam MM. Primary Progressive Aphasia and the Language Network: the 2013 H. Houston Merritt Lecture. Neurology 2013; 81:456.
8. Finger, Elizabeth C. “Frontotemporal Dementias.” Continuum :Lifelong Learning in Neurology 22.2 Dementia (2016): 464–489. PMC. Web. 21 Aug. 2017. 
9. Hodges JR, Patterson K. Semantic dementia: a uniqueclinicopathological syndrome. Lancet Neurology 2007;6:1004-1014.
10. Gorno-TempiniML, Hillis AE, Weintraub S, et al. Classification of Primary Progressive Aphasia and Its Variants. Neurology 2011; 76:1006. 
11. Rohrer, Jonathan D. et al. “Word-Finding Difficulty: A Clinical Analysis of the Progressive Aphasias.” Brain :a journal of neurology 131.Pt 1 (2008): 8–38. PMC. Web. 21 Aug. 2017. 
12. MesulamMM, Grossman M, Hillis A, et al. The Core and Halo of Primary Progressive Aphasia and Semantic Dementia. Ann Neurol 2003; 54 Suppl 5:S11.  
13. Boxer, Adam, MD. “Frontotemporal Dementia withGranulin Mutation Trial of a Histone Deacetylase Inhibitor.” UCSF Memory and Aging Center. University of California San Francisco, 5 May 2016. Web. 04 Apr. 2017. <http//memory.ucsf.edu/research/clinical-trials/frm0334>.
14. ClinicalTrials.gov. Impact of Emotional Mimicry and Oxytocin on Frontotemporal Dementia (IEMO). <https://clinicaltrials.gov/ct2/show/NCT01937013?term=intranasal+oxytocin&rank=31>.
15. Adler G, Angelika EM. Improvement in behavioral symptoms, motor impairment and activities of daily living in a patient with the behavioral variant of frontotemporal dementia under treatment with methylene blue. Geriatric Mental Health Care 2014;2(1): 1-2.
16. ClinicalTrials.gov. Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia (Lithium). <https://clinicaltrials.gov/ct2/show/NCT02862210?term=frontotemporal+dementia&rank=9>.

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