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During reward processing individuals weigh positive and negative features of a stimulus to determine whether they will pursue or avoid it. Though patients with behavioural variant frontotemporal dementia display changes in their pursuit of rewards, such as food, alcohol, money, and sex, the basis for these shifts is not clearly established. In particular, it is unknown whether patients' behaviour results from excessive focus on rewards, insensitivity to punishment, or to dysfunction in a particular stage of reward processing, such as anticipation, consumption, or action selection. Our goal was to determine the nature of the reward deficit in behavioural variant frontotemporal dementia and its underlying anatomy. We devised a series of tasks involving pleasant, unpleasant, and neutral olfactory stimuli, designed to separate distinct phases of reward processing. In a group of 25 patients with behavioural variant frontotemporal dementia and 21 control subjects, diagnosis by valence interactions revealed that patients with behavioural variant frontotemporal dementia rated unpleasant odours as less aversive than did controls and displayed lower skin conductance responses when anticipating an upcoming aversive odour. Subjective pleasantness ratings and skin conductance responses did not differ between behavioural variant frontotemporal dementia and controls for pleasant or neutral smells. In a task designed to measure the effort subjects would expend to smell or avoid smelling a stimulus, patients with behavioural variant frontotemporal dementia were less motivated, and therefore less successful than control subjects, at avoiding what they preferred not to smell, but had equivalent success at obtaining stimuli they found rewarding. Voxel-based morphometry of patients with behavioural variant frontotemporal dementia revealed that the inability to subjectively differentiate the valence of pleasant and unpleasant odours correlated with atrophy in right ventral mid-insula and right amygdala. High pleasantness ratings of unpleasant stimuli correlated with left dorsal anterior insula and frontal pole atrophy. These findings indicate that insensitivity to negative information may be a key component of the reward-seeking behaviours in behavioural variant frontotemporal dementia, and may relate to degeneration of structures that are involved in representing the emotional salience of sensory information.

Author(s): Sturm, Virginia E; Perry, David C; Wood, Kristie; Hua, Alice Y; Alcantar, Oscar; Datta, Samir; Rankin, Katherine P; Rosen, Howard J; Miller, Bruce L; Kramer, Joel H | Abstract: IntroductionEmpathy and shared feelings of reward motivate individuals to share resources with others when material gain is not at stake. Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disease that affects emotion- and reward-relevant neural systems. Although there is diminished empathy and altered reward processing in bvFTD, how the disease impacts prosocial behavior is less well understood.MethodsA total of 74 participants (20 bvFTD, 15 Alzheimer's disease [AD], and 39 healthy controls) participated in this study. Inspired by token-based paradigms from animal studies, we developed a novel task to measure prosocial giving (the "Giving Game"). On each trial of the Giving Game, participants decided how much money to offer to the experimenter, and prosocial giving was the total amount that participants gave to the experimenter when it cost them nothing to give. Voxel-based morphometry was then used to identify brain regions that were associated with prosocial giving.ResultsProsocial giving was lower in bvFTD than in healthy controls; prosocial giving in AD did not differ significantly from either of the other groups. Whereas lower prosocial giving was associated with atrophy in the right pulvinar nucleus of the thalamus, greater prosocial giving was associated with atrophy in the left ventral striatum.ConclusionThese findings suggest that simple acts of generosity deteriorate in bvFTD due to lateralized atrophy in reward-relevant neural systems that promote shared feelings of positive affect.

Executive functions refer to a constellation of higher-level cognitive abilities that enable goal-oriented behavior. The NIH EXAMINER battery was designed to assess executive functions comprehensively and efficiently. Performance can be summarized by a single score, the “Executive Composite,” which combines measures of inhibition, set-shifting, fluency, and working memory. We evaluated the ecological validity of the Executive Composite in a sample of 225 mixed neurological patients and controls using the Frontal Systems Behavior Scale (FrSBe), an informant-based measure of real-world executive behavior. In addition, we investigated the neuroanatomical correlates of the Executive Composite using voxel-based morphometry in a sample of 37 participants diagnosed with dementia, mild cognitive impairment, or as neurologically healthy. The Executive Composite accounted for 28% of the variance in Frontal Systems Behavior Scale scores beyond age. Even after including two widely used executive function tests (Trails B and Stroop) as covariates, the Executive Composite remained a significant predictor of real-world behavior. Anatomically, poorer scores on the Executive Composite were associated with smaller right and left dorsolateral prefrontal volumes, brain regions critical for good executive control. Taken together, these results suggest that the Executive Composite measures important aspects of executive function not captured by standard measures and reflects the integrity of frontal systems. (JINS, 2013,19, 1–9)

© 2015 The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. Many neuropsychiatric disorders are marked by abnormal behaviour and decision-making, but prevailing diagnostic criteria for such behaviours are typically qualitative and often ambiguous. Behavioural variant frontotemporal dementia and semantic variant primary progressive aphasia (also called semantic dementia) are two clinical variants of frontotemporal dementia with overlapping but distinct anatomical substrates known to cause profound changes in decision-making. We investigated whether abnormal decision-making in these syndromes could be more precisely characterized in terms of dissociable abnormalities in patients' subjective evaluations of valence (positive versus negative outcome) and of time (present versus future outcome). We presented 28 patients with behavioural variant frontotemporal dementia, 14 patients with semantic variant primary progressive aphasia, 25 patients with Alzheimer's disease (as disease controls), and 61 healthy older control subjects with experimental tasks assaying loss aversion and delay discounting. In general linear models controlling for age, gender, education and Mini-Mental State Examination score, patients with behavioural variant frontotemporal dementia were less averse to losses than control subjects (P < 0.001), while patients with semantic variant primary progressive aphasia discounted delayed rewards more steeply than controls (P = 0.019). There was no relationship between loss aversion and delay discounting across the sample, nor in any of the subgroups. These findings suggest that abnormal behaviours in neurodegenerative disease may result from the disruption of either of two dissociable neural processes for evaluating the outcomes of action. More broadly, these findings suggest a role for computational methods to supplement traditional qualitative characterizations in the differential diagnosis of neuropsychiatric disorders.

Author(s): Perry, David C; Sturm, Virginia E; Wood, Kristie A; Miller, Bruce L; Kramer, Joel H

We investigated the viability of psychometrically robust executive function measures as markers for premanifest Huntington's disease (HD).Fifteen premanifest HD subjects and 42 controls were compared on the NIH EXAMINER executive function battery. This battery yields an overall executive composite score, plus working memory, cognitive control, and fluency scores that are measured on psychometrically matched scales. The scores were correlated with two disease markers, disease burden and striatal volumes, in the premanifest HD subjects.The premanifest HD subjects scored significantly lower on the working memory score. The executive composite positively correlated with striatal volumes, and the working memory score negatively correlated with disease burden. The cognitive control and fluency scores did not differ between the groups or correlate significantly with the disease markers.The NIH EXAMINER executive composite and working memory scores are sensitive markers of cognitive dysfunction, striatal volume, and disease burden in premanifest HD.

Objective: The objective of this study was to determine which aspects of executive functions are most affected in behavioral variant frontotemporal dementia (bvFTD) and best differentiate this syndrome from Alzheimer disease (AD). Methods: We compared executive functions in 22 patients diagnosed with bvFTD, 26 with AD, and 31 neurologically healthy controls using a conceptually driven and comprehensive battery of executive function tests, the NIH EXAMINER battery (http://examiner.ucsf.edu). Results: The bvFTD and the AD patients were similarly impaired compared with controls on tests of working memory, category fluency, and attention, but the patients with bvFTD showed significantly more severe impairments than the patients with AD on tests of letter fluency, antisaccade accuracy, social decision-making, and social behavior. Discriminant function analysis with jackknifed cross-validation classified the bvFTD and AD patient groups with 73% accuracy. Conclusions: Executive function assessment can support bvFTD diagnosis when measures are carefully selected to emphasize frontally specific functions.