Conflict monitoring in early frontotemporal dementia

Memory and Aging Center, UCSF Department of Neurology, San Francisco, CA, USA.
Neurology (Impact Factor: 8.29). 09/2009; 73(5):349-55. DOI: 10.1212/WNL.0b013e3181b04b24
Source: PubMed


Despite the extensive frontal atrophy and behavioral disinhibition that characterizes behavioral variant frontotemporal dementia (bvFTD), many studies of early bvFTD suggest normal executive functioning (EF). The current study examined cognitive control in patients with bvFTD who otherwise seemed cognitively normal.
Subjects included 7 patients with bvFTD with normal neuropsychological test scores, 7 patients with bvFTD matched for Mini-Mental State Examination score but with impaired neuropsychological test scores, and 14 normal controls. A flanker paradigm and other measures of EF were administered to participants. A semiautomated parcellation program was used to analyze structural MRI scans.
On the flanker task, multivariate analysis of variance revealed a significant condition X diagnosis interaction. Both bvFTD groups showed a larger congruency effect than normal controls, i.e., they displayed disproportionately reduced speed and accuracy on incongruent trials relative to congruent trials. Imaging data illustrated significant orbitofrontal atrophy in patients with early bvFTD as compared with controls.
Patients with behavioral variant frontotemporal dementia (bvFTD) who performed within normal limits on clinical tests of executive functioning demonstrated a select impairment on an experimental test of cognitive control, suggesting a subtle impairment in inhibiting attention or response to the irrelevant stimuli. Measures of neuropsychological functioning sensitive to the ventromedial prefrontal cortex may be useful in early diagnosis of patients with bvFTD. Our understanding of this syndrome may be increased by considering the efficiency of selective inhibition, a fundamental component of executive cognitive control.

  • Source
    • "It is to be determined whether the region-specific inhibition of PCA simply reflects differential levels of translated RGS4 or depends on characteristic distribution patterns of PCA perhaps through neuronal transport systems in brain capillary membranes. It is interesting that these regions are also known to be critically affected by various neurodegenerative diseases such as Alzheimer's disease (AD), ALS, and FTLD-U4142. To identify putative GPCR target genes altered by PCA treatment in the brain, we profiled the expression of genes in the frontal cortex and hippocampus by microarray analysis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In the arginylation branch of the N-end rule pathway, unacetylated N-terminal destabilizing residues function as essential determinants of protein degradation signals (N-degron). Here, we show that a neurostimulant, para-chloroamphetamine (PCA), specifically inhibits the Arg/N-end rule pathway, delaying the degradation of its artificial and physiological substrates, including regulators of G protein signaling 4 (RGS4), in vitro and in cultured cells. In silico computational analysis indicated that PCA strongly interacts with both UBR box and ClpS box, which bind to type 1 and type 2 N-degrons, respectively. Moreover, intraperitoneal injection of PCA significantly stabilized endogenous RGS4 proteins in the whole mouse brain and, particularly, in the frontal cortex and hippocampus. Consistent with the role of RGS4 in G protein signaling, treatment with PCA impaired the activations of GPCR downstream effectors in N2A cells, phenocopying ATE1-null mutants. In addition, levels of pathological C-terminal fragments of TDP43 bearing N-degrons (Arg208-TDP25) were significantly elevated in the presence of PCA. Thus, our study identifies PCA as a potential tool to understand and modulate various pathological processes regulated by the Arg/N-end rule pathway, including neurodegenerative processes in FTLD-U and ALS.
    Full-text · Article · Sep 2014 · Scientific Reports
  • Source
    • "As the median of the population was more robust, it was more appropriate to use the median rather than the mean to determine an ''average''; thus, the median response time and response accuracy were analyzed using a multivariate analysis of covariance (MANCOVA). For this analysis, the diagnosis (AD, MCI, and NC) was the between-subject factor and the conditions (target-alone , neutral, congruent and incongruent) were a within-subject factor, with age and the Mini-Mental State Examination (MMSE) being included as covariates (Krueger et al., 2009). When a significant multivariate main effect was detected with MANCOVA, additional univariate ANCOVAs were performed to elucidate differences in either the response times or accuracy with a between-subject factor group with any two of three possible levels and a within-subject factor with any two of four levels. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The ability to resolve conflicts is indispensable to the function of daily life and decreases with cognitive decline. We hypothesized that subjects with different levels of cognitive impairment exhibit different conflict resolution performances and may be susceptible to interference effects at different stages. Sixteen normal controls (NC), 15 mild cognitive impairment (MCI) and seven Alzheimer's disease (AD) patients were recruited to perform in a modified Eriksen flanker task. We observed that the AD and MCI patients exhibited smaller accuracy rate and longer response time compared to NC subjects. Longer N2 and P300 latencies were observed in the AD group. Furthermore, the MCI group showed a longer latency than the NC group in the P300 latency. The magnitude of the perceptual and response interference effects was larger in the AD group than the other groups, and the MCI group significantly differed from the NC group at the perceptual level. The ability to resolve conflict decreased with impaired cognition and the perceptual and response interference effects may be useful in distinguishing MCI and AD. The perceptual or response interference effect may potentially be employed as a useful non-invasive probe for the clinical diagnosis of MCI and AD.
    Full-text · Article · Jun 2013 · Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology
  • Source
    • "Inhibitory control can be lost in neuropsychiatric patients or monkeys with frontal damage or dysfunction (Caycedo, Miller, Kramer, & Rascovsky, 2009; Krueger et al., 2009; Aron & Poldrack, 2005; Meunier, Bachevalier, & Mishkin, 1997; Iversen & Mishkin, 1970). Neural correlates of associative learning without reversals are seen in many brain areas (such as the medial-temporal lobe and BG) and damage to any of these areas can disrupt learning (Bedard & Sanes, 2009; Cohn, McAndrews, & Moscovitch, 2009; Braun et al., 2008; Finke et al., 2008; Aosaki et al., 1994; Murray, Gaffan, & Mishkin, 1993). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The PFC plays a central role in our ability to learn arbitrary rules, such as "green means go." Previous experiments from our laboratory have used conditional association learning to show that slow, gradual changes in PFC neural activity mirror monkeys' slow acquisition of associations. These previous experiments required monkeys to repeatedly reverse the cue-saccade associations, an ability known to be PFC-dependent. We aimed to test whether the relationship between PFC neural activity and behavior was due to the reversal requirement, so monkeys were trained to learn several new conditional cue-saccade associations without reversing them. Learning-related changes in PFC activity now appeared earlier and more suddenly in correspondence with similar changes in behavioral improvement. This suggests that learning of conditional associations is linked to PFC activity regardless of whether reversals are required. However, when previous learning does not need to be suppressed, PFC acquires associations more rapidly.
    Full-text · Article · Jul 2011 · Journal of Cognitive Neuroscience
Show more

We use cookies to give you the best possible experience on ResearchGate. Read our cookies policy to learn more.