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Divergent Social Functioning in Behavioral Variant Frontotemporal Dementia and Alzheimer Disease: Reciprocal Networks and Neuronal Evolution William W

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Divergent Social Functioning in Behavioral Variant Frontotemporal Dementia and Alzheimer Disease: Reciprocal Networks and Neuronal Evolution William W ORIGINAL ARTICLE Divergent Social Functioning in Behavioral Variant Frontotemporal Dementia and Alzheimer Disease: Reciprocal Networks and Neuronal Evolution William W. Seeley, MD,*w John M. Allman, PhD,z Danielle A. Carlin, MD,wy Richard K. Crawford, BS,*w Marcelo N. Macedo, BS,*w Michael D. Greicius, MD,J Stephen J. DeArmond, MD, PhD,z and Bruce L. Miller, MD*w (Alzheimer Dis Assoc Disord 2007;21:S50–S57) Abstract: Behavioral variant frontotemporal dementia (bvFTD) disrupts our most human social and emotional functions. Early in the disease, patients show focal anterior cingulate cortex he slow churn of evolution has rendered a human (ACC) and orbital frontoinsula (FI) degeneration, accentuated Tbrain with remarkable flexibility. Like other primates in the right hemisphere. The ACC and FI, though sometimes and many mammals, we can manage dynamic, immediate considered ancient in phylogeny, feature a large bipolar stimuli and contexts using a fluid mix of cognitive and projection neuron, the von Economo neuron (VEN), which is emotional processing. Humans and great apes may differ found only in humans, apes, and selected whales—all large- even from other primates, however, in their ability to brained mammals with complex social structures. In contrast to represent the mental and emotional contents of the self bvFTD, Alzheimer disease (AD) often spares social functioning, and others1 and to use self-anchored, visceral-autonomic, and the ACC and FI, until late in its course, damaging instead a emotional salience assessments to reach decisions that posterior hippocampal-cingulo-temporal-parietal network serve both short- and long-term personal objectives. In involved in episodic memory retrieval. These divergent patterns parallel with these achievements, the human brain has of functional and regional impairment remain mysterious evolved the capacity to perform mental time travel.2 despite extensive molecular-level characterization of bvFTD Thought by some to further distinguish humans,3 and and AD. In this report, we further develop the hypothesis that possibly apes,4 from other species, mental time travel VENs drive the regional vulnerability pattern seen in bvFTD, refers to projection of the self into one’s personal past and citing recent evidence from functional imaging in healthy future. The dementias can slowly undermine each of these humans, and also structural imaging and quantitative neuro- recently evolved capacities, and this observation is the pathology data from bvFTD and AD. Our most recent findings main theme of this manuscript. suggest that bvFTD and AD target distinct, anticorrelated In neurodegenerative diseases, genetic-molecular intrinsic connectivity networks and that bvFTD-related VEN aberrations undermine specific neurons within specific injury occurs throughout the ACC-FI network. We suggest that brain regions. These changes disrupt function-critical the regional and neuronal vulnerability patterns seen in bvFTD neural networks, producing signature patterns of cogni- and AD underlie the divergent impact of these disorders on tive or behavioral impairment. In this report, we highlight recently evolved social-emotional functions. selective vulnerability in behavioral variant frontotem- Key Words: von Economo neuron, frontotemporal dementia, poral dementia (bvFTD) and Alzheimer disease (AD), the Alzheimer disease, anterior cingulate, frontoinsula most common dementia syndromes in patients less than 65 years of age.5 We describe how these disorders produce contrasting patterns of behavioral, regional, and cellular From the Departments of *Neurology; yPsychiatry; zPathology, level impairment that reflect divergent assaults on ‘‘here University of California at San Francisco; wUCSF Memory and and now’’ (emotional salience assessment) versus ‘‘there Aging Center, San Francisco; zDivision of Biology, California and then’’ (mental time travel) processing. Institute of Technology, Pasadena; and JDepartments of Neurology and Psychiatry, Stanford University School of Medicine, Stanford, CA. SOCIAL FUNCTIONING DIFFERENCES IN bvFTD Supported by the National Institute of Aging grants K08 AG027086-01, 1P01 AG19724-01A1, and P50 AG1657303-75271, Larry L. Hillblom AND AD REFLECT CONTRASTING REGIONAL Foundation, James S. McDonnell Foundation, Doris Duke VULNERABILITY PATTERNS Foundation, Gordon and Betty Moore Foundation, and the BvFTD is the commonest of 3 clinical syndromes David and Lucile Packard Foundation. caused by underlying frontotemporal lobar degeneration Reprints: William W. Seeley, MD, UCSF Department of Neurology, Memory and Aging Center, 350 Parnassus Ave., Suite 706, Box 1207, pathology. Patients with bvFTD develop early impair- San Francisco, CA 94143-1207 (e-mail: [email protected]). ments in social cognitive and emotional functions, includ- Copyright r 2007 by Lippincott Williams & Wilkins ing self-conscious emotions, such as embarrassment6; S50 Alzheimer Dis Assoc Disord Volume 21, Number 4, October–December 2007 Alzheimer Dis Assoc Disord Volume 21, Number 4, October–December 2007 Reciprocal Networks and Neuronal Evolution theory of mind7,8; empathy7,9; metacognitive judgment, In contrast, dorsolateral prefrontal regions critical for including awareness of deficit8 and moral sensibility.7,10 executive functioning are affected in both disorders,34 Patients may even develop shifts in long-held core aspects explaining why social, not cognitive, frontal functions of their personal identity, especially when asymmetric right help differentiate bvFTD from AD.35 For all of these hemisphere involvement is seen.11 These deficits suggest reasons, studying the ACC and FI may reveal factors that impairment in the brain’s ability to represent the self (both affect neuron survival (for better or worse) in neurode- viscerally and abstractly) and to represent the feelings and generative disease. thoughts of others.12 During development, as in phylo- geny, many aspects of self- and other-representation emerge late. Infants achieve mirror self-recognition at 15 HUMAN FUNCTIONAL NETWORK to 24 months of age, providing a necessary substrate for ARCHITECTURES RELATED TO bvFTD AND AD the self-conscious emotions, such and embarrassment and Functional imaging studies suggest that a basic role shame, that follow.13 Patients with early bvFTD often of the frontal paralimbic cortex is to generate, through retain core autonomic reflexes yet prove difficult to ACC, and re-represent, via FI, visceral-autonomic embarrass,6 perhaps because they cannot perceive the responses.36–38 Adaptive human behavior may rely on social-emotional significance of their own actions. Even integration of these body state signals with social stimuli, more intriguingly, some patients can articulate the precise situational context, and long-term personal goals. Con- feelings of others’ (eg, their spouse’s distress) yet lack the sistent with these ideas, ACC and FI activate in response emotional and behavioral responses normally evoked by to diverse forms of biologic salience, including the those feelings. These selective social-emotional deficits arise emotional aspects of pain23,39; metabolic stress40; sensual in parallel with consistent14 and severe15,16 anterior touch41; faces of loved ones,42 allies,43 or rivals44; and cingulate cortex (ACC) and orbital frontalinsula (FI) certain forms of uncertainty45 and task set engagement.46 degeneration. Previous pathologic studies have suggested In essence, ACC and FI are engaged as one enters the that medial frontal and orbital frontoinsular regions are here and now to deal with some salient cognitive, also the sites where bvFTD-related atrophy begins.17,18 homeostatic, or emotional demand.47,48 We and others Consistent with this idea, we recently showed that patients have shown that ACC and FI anchor an intrinsic with very mild bvFTD (Clinical Dementia Rating scale connectivity network (ICN) in healthy humans, detect- score = 0.5) feature ACC/FI atrophy, accompanied by able using functional connectivity analysis of task-free focal frontal pole, rostromedial and dorsolateral prefron- functional magnetic resonance imaging (fMRI) data.48,49 tal, striatal, and thalamic injury.19 These early-affected Here and now dealings are perturbed in patients with regions may represent an anterior brain system for social- bvFTD, for whom serious social transgressions7,10 and emotional functioning,20 with a particular emphasis on even threats to homeostasis50 lack emotional weight. regions that support visceral self- and other-representa- A posterior ICN, closely related to the regions tion.21–23 Notably, while this anterior network degenerates, affected in AD, has received greater attention51,52 than posterior cortical functions survive or even thrive, at times the paralimbic ‘‘emotional salience network’’48 and associated with emergent visual creativity.24 routinely deactivates during tasks that activate the ACC AD, in contrast, begins with episodic memory and FI.42,53 This network, sometimes referred to as the dysfunction and impaired mental time travel, accompa- default mode network (DMN), is made up of the nied by neuropathologic,25,26 metabolic,27 and functional hippocampi, PCC/preCu, lateral parietal regions, and connectivity28 changes within the medial temporal lobe. rostromedial prefrontal cortex (rmPFC), structures cri- Entorhinal cortex layer 2 pyramidal projection neurons tical for episodic memory formation and retrieval, mental show early tangle formation and neuronal dropout.26 In imagery, and reflective contemplation.30,53–55
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