guistic abilities. Interestingly, these individuals often respond to questions in a manner that is opposite of their intention, typically saying “yes” when they mean “no” and vice versa. Their brain imaging shows asymmetric frontal or insular atrophy, although the degree of atrophy can be quite subtle early in the course. The nonfluent/agrammatic variant of PPA is almost always due to one of the frontotemporal degenerations. The other distinctive PPA that is invariably due to a frontotemporal degeneration is the semantic variant of PPA. In this disorder, the affected individuals have normal-sounding speech but they experience an erosion of their vocabulary and their understanding of the meaning of words and objects. The most common and dramatic illustration of this loss is when an examiner asks the patient to say what an object, such as a watch, is used for. The patient with semantic variant PPA will reply, “A watch? What’s a watch?” There are other patterns of progressive aphasia where word selection in spontaneous speech is impoverished, called logopenic PPA. Interestingly, this form of PPA can be due to Alzheimer’s or to frontotemporal degeneration. Progressive supranuclear palsy, corticobasal syndrome, and amyotrophic lateral sclerosis. The frontotemporal degenerations also include progressive supranuclear palsy syndrome and corticobasal syndrome. Although these conditions were originally described as movement disorders, many or most individuals with one of these syndromes also have some form of dementia. The pathology of both of these disorders is that of frontotemporal degeneration. While it might seem over-reaching to call amyotrophic lateral sclerosis (ALS) one of the frontotemporal degenerations, the fact is that many patients with typical ALS have changes in behavior and cognition if those symptoms are
actually sought. And, importantly, the most common cause of familial ALS is the same mutation that is the most common cause of familial frontotemporal degeneration. The pathology in motor neurons in ALS is identical to that of one of the frontotemporal degeneration subtypes. Motor neuron disease has long been recognized in people with rapidly progressive forms of frontotemporal degeneration. A transformation in understanding A half-dozen pivotal discoveries in the past 15 years have transformed our understanding of the neuropathology of frontotemporal degeneration from the 19th-century discovery of the Pick body to a 21st-century multidimensional molecular model. The first protein to be implicated in frontotemporal degeneration was the microtubule-associated protein tau (MAPT). Mutations in the MAPT gene were shown to cause many cases of frontotemporal degeneration. Two species of the tau protein, one with 3 repeating (3-R) units and another with 4 repeating (4-R) units, were shown to make up the pathological intra- and extra-cellular protein deposits in Pick’s disease (a 3-R tauopathy), progressive supranuclear palsy and corticobasal degeneration (both 4-R tauopathies) and cases with mutations in the MAPT gene (also 4-R tauopathies). It so happened that Pick’s disease, the “grand-daddy” of frontotemporal degeneration, developed silver-staining positive round intraneuronal inclusions, that enabled Arnold Pick and Alois Alzheimer to recognize the disorder using classical histopathological techniques, more than 100 years ago. About half of cases of frontotemporal degeneration tauopathies are genetic, while the others are apparently sporadic. Another major discovery was that many cases of frontotemporal degeneration showed tau-negative intracellular protein inclusions containing a protein called transactive
Figure 1. MR scan showing frontal atrophy typical of what occurs in patients with behavior variant frontotemporal dementia
response DNA binding protein of 43 kilodalton molecular weight (TDP-43). About two-thirds of all frontotemporal degeneration involves abnormal intracellular cytoplasmic aggregates of TDP-43. Two genetic discoveries
subsequently linked abnormal accumulation of cytoplasmic TDP-43 with mutations in the gene granulin (GRN) (also termed progranulin and abbreviated as PGRN) and the gene chromosome 9 open reading
The frontotemporal degenerations to page 30
Psychiatrist Cross-Cultural Medicine HealthPartners Medical Group in St. Paul, Minnesota, seeks a BC/BE licensed psychiatrist to practice cross-cultural medicine with our experienced Behavioral Health team at the Center for International Health (CIH), an internationally recognized refugee/immigrant medicine clinic which has helped define best practices in refugee and immigrant healthcare for 30+ years. U.S. and international experience providing psychiatric care to refugees and globally mobile populations is strongly preferred. Qualified bilingual psychiatrists (especially those fluent in Somali, Khmer, Oromo, Karen, Vietnamese, Hmong, Nepali or Russian) are encouraged to apply. This part-time (0.5 FTE) position will provide outpatient psychiatric care closely integrated with primary care in a holistic care model, while partnering with community organizations and the MN Department of Health’s Refugee Health Program. There is also opportunity for an academic faculty appointment at the University of MN and teaching involvement in the Global Health Pathway (www.globalhealth.umn.edu). HealthPartners offers a rewarding practice with a competitive salary and benefits package. Forward your CV and cover letter, specifying your language fluency and global health/refugee medicine experience, to lori.m.fake@healthpartners.com or apply online at healthpartners.com/ careers. For more details, call 800-472-4695 x1. EOE
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