María Roca

Chlorophyll breakdown: Pheophorbide a oxygenase is a Rieske-type iron-sulfur protein, encoded by the accelerated cell death 1 gene

Chlorophyll (chl) breakdown during senescence is an integral part of plant development and leads to the accumulation of colorless catabolites. The loss of green pigment is due to an oxygenolytic opening of the porphyrin macrocycle of pheophorbide (pheide) a followed by a reduction to yield a fluorescent chl catabolite. This step is comprised of the interaction of two enzymes, pheide a oxygenase (PaO) and red chl catabolite reductase. PaO activity is found only during senescence, hence PaO seems to be a key regulator of chl catabolism. Whereas red chl catabolite reductase has been cloned, the nature of PaO has remained elusive. Here we report on the identification of the PaO gene of Arabidopsis thaliana (AtPaO). AtPaO is a Rieske-type iron–sulfur cluster-containing enzyme that is identical to Arabidopsis accelerated cell death 1 and homologous to lethal leaf spot 1 (LLS1) of maize. Biochemical properties of recombinant AtPaO were identical to PaO isolated from a natural source. Production of fluorescent chl catabolite-1 required ferredoxin as an electron source and both substrates, pheide a and molecular oxygen. By using a maize lls1 mutant, the in vivo function of PaO, i.e., degradation of pheide a during senescence, could be confirmed. Thus, lls1 leaves stayed green during dark incubation and accumulated pheide a that caused a light-dependent lesion mimic phenotype. Whereas proteins were degraded similarly in wild type and lls1, a chl-binding protein was selectively retained in the mutant. PaO expression correlated positively with senescence, but the enzyme appeared to be post-translationally regulated as well.

A neuropsychological battery to detect specific executive and social cognitive impairments in early frontotemporal dementia

Traditional cognitive tests may not be sensitive for the early detection of executive and social cognitive impairments in the behavioural variant of frontotemporal dementia. The aim of this study was to detect specific executive and social cognitive deficits in patients with early behavioural variant frontotemporal dementia using a battery of tests previously shown to be sensitive to frontal lobe dysfunction. Behavioural variant frontotemporal dementia patients and paired controls were assessed with a complete standard neuropsychological battery evaluating attention, memory, visuospatial abilities, language and executive functions. All participants were then assessed with our Executive and Social Cognition Battery, which included Theory of Mind tests (Mind in the Eyes, Faux Pas), the Hotel Task, Multiple Errands Task-hospital version and the Iowa Gambling Task for complex decision-making. Patients were divided into two groups according to their Addenbrookes Cognitive Examination scores, a measure of general cognitive status. Low Addenbrookes Cognitive Examination patients differed from controls on most tasks of the standard battery and the Executive and Social Cognition Battery. While high Addenbrookes Cognitive Examination patients did not differ from controls on most traditional neuropsychological tests, significant differences were found between this high-functioning behavioural variant of frontotemporal dementia group and controls on most measures of our Executive and Social Cognition Battery. Our results suggest that the Executive and Social Cognition Battery used in this study is more sensitive in detecting executive and social cognitive impairment deficits in early behavioural variant of frontotemporal dementia than the classical cognitive measures.

Executive function and fluid intelligence after frontal lobe lesions.

Many tests of specific ‘executive functions’ show deficits after frontal lobe lesions. These deficits appear on a background of reduced fluid intelligence, best measured with tests of novel problem solving. For a range of specific executive tests, we ask how far frontal deficits can be explained by a general fluid intelligence loss. For some widely used tests, e.g. Wisconsin Card Sorting, we find that fluid intelligence entirely explains frontal deficits. When patients and controls are matched on fluid intelligence, no further frontal deficit remains. For these tasks too, deficits are unrelated to lesion location within the frontal lobe. A second group of tasks, including tests of both cognitive (e.g. Hotel, Proverbs) and social (Faux Pas) function, shows a different pattern. Deficits are not fully explained by fluid intelligence and the data suggest association with lesions in the right anterior frontal cortex. Understanding of frontal lobe deficits may be clarified by separating reduced fluid intelligence, important in most or all tasks, from other more specific impairments and their associated regions of damage.

Decision-making cognition in neurodegenerative diseases

A large proportion of human social neuroscience research has focused on the issue of decision-making. Impaired decision-making is a symptomatic feature of a number of neurodegenerative diseases, but the nature of these decision-making deficits depends on the particular disease. Thus, examining the qualitative differences in decision-making impairments associated with different neurodegenerative diseases could provide valuable information regarding the underlying neural basis of decision-making. Nevertheless, few comparative reports of decision-making across patient groups exist. In this Review, we examine the neuroanatomical substrates of decision-making in relation to the neuropathological changes that occur in Alzheimer disease, frontotemporal dementia, Parkinson disease and Huntington disease. We then examine the main findings from studies of decision-making in these neurodegenerative diseases. Finally, we suggest a number of recommendations that future studies could adopt to aid our understanding of decision-making cognition.

INECO Frontal Screening (IFS): A brief, sensitive, and specific tool to assess executive functions in dementia–CORRECTED VERSION

Although several brief sensitive screening tools are available to detect cognitive dysfunction, few have been developed to quickly assess executive functioning (EF) per se. We designed a new brief tool to evaluate EF in neurodegenerative diseases. Patients with an established diagnosis of behavioral variant frontotemporal dementia (bvFTD; n = 22), Alzheimer disease (AD; n = 25), and controls (n = 26) were assessed with a cognitive screening test, the INECO Frontal Screening (IFS), and EF tests. Clinical Dementia Rating Scale (CDR) scores were obtained for all patients. Internal consistency of the IFS was very good (Cronbachs alpha = .80). IFS total (out of 30 points) was 27.4 (SD = 1.6) for controls, 15.6 (SD = 4.2) for bvFTD, and 20.1 (SD = 4.7) for AD. Using a cutoff of 25 points, sensitivity of the IFS was 96.2%, and specificity 91.5% in differentiating controls from patients with dementia. The IFS correlated significantly with the CDR and executive tasks. The IFS total discriminated controls from demented patients, and bvFTD from AD. IFS is a brief, sensitive, and specific tool for the detection of executive dysfunction associated with neurodegenerative diseases. The IFS may be helpful in the differential diagnosis of FTD and AD.

Fluid intelligence loss linked to restricted regions of damage within frontal and parietal cortex

Tests of fluid intelligence predict success in a wide range of cognitive activities. Much uncertainty has surrounded brain lesions producing deficits in these tests, with standard group comparisons delivering no clear result. Based on findings from functional imaging, we propose that the uncertainty of lesion data may arise from the specificity and complexity of the relevant neural circuit. Fluid intelligence tests give a characteristic pattern of activity in posterolateral frontal, dorsomedial frontal, and midparietal cortex. To test the causal role of these regions, we examined fluid intelligence in 80 patients with focal cortical lesions. Damage to each of the proposed regions predicted fluid intelligence loss, whereas damage outside these regions was not predictive. The results suggest that coarse group comparisons (e.g., frontal vs. posterior) cannot show the neural underpinnings of fluid intelligence tests. Instead, deficits reflect the extent of damage to a restricted but complex brain circuit comprising specific regions within both frontal and posterior cortex.

Motor-language coupling: direct evidence from early Parkinson’s disease and intracranial cortical recordings

Language and action systems are functionally coupled in the brain as demonstrated by converging evidence using Functional magnetic resonance imaging (fMRI), electroencephalography (EEG), transcranial magnetic stimulation (TMS), and lesion studies. In particular, this coupling has been demonstrated using the action-sentence compatibility effect (ACE) in which motor activity and language interact. The ACE task requires participants to listen to sentences that described actions typically performed with an open hand (e.g., clapping), a closed hand (e.g., hammering), or without any hand action (neutral); and to press a large button with either an open hand position or closed hand position immediately upon comprehending each sentence. The ACE is defined as a longer reaction time (RT) in the action-sentence incompatible conditions than in the compatible conditions. Here we investigated direct motor-language coupling in two novel and uniquely informative ways. First, we measured the behavioural ACE in patients with motor impairment (early Parkinsons disease - EPD), and second, in epileptic patients with direct electrocorticography (ECoG) recordings. In experiment 1, EPD participants with preserved general cognitive repertoire, showed a much diminished ACE relative to non-EPD volunteers. Moreover, a correlation between ACE performance and action-verb processing (kissing and dancing test - KDT) was observed. Direct cortical recordings (ECoG) in motor and language areas (experiment 2) demonstrated simultaneous bidirectional effects: motor preparation affected language processing (N400 at left inferior frontal gyrus and middle/superior temporal gyrus), and language processing affected activity in movement-related areas (motor potential at premotor and M1). Our findings show that the ACE paradigm requires ongoing integration of preserved motor and language coupling (abolished in EPD) and engages motor-temporal cortices in a bidirectional way. In addition, both experiments suggest the presence of a motor-language network which is not restricted to somatotopically defined brain areas. These results open new pathways in the fields of motor diseases, theoretical approaches to language understanding, and models of action-perception coupling.

The role of Area 10 (BA10) in human multitasking and in social cognition: a lesion study.

A role for rostral prefrontal cortex (BA10) has been proposed in multitasking, in particular, the selection and maintenance of higher order internal goals while other sub-goals are being performed. BA10 has also been implicated in the ability to infer someone elses feelings and thoughts, often referred to as theory of mind. While most of the data to support these views come from functional neuroimaging studies, lesion studies are scant. In the present study, we compared the performance of a group of frontal patients whose lesions involved BA10, a group of frontal patients whose lesions did not affect this area (nonBA10), and a group of healthy controls on tests requiring multitasking and complex theory of mind judgments. Only the group with lesions involving BA10 showed deficits on multitasking and theory of mind tasks when compared with control subjects. NonBA10 patients performed more poorly than controls on an executive function screening tool, particularly on measures of response inhibition and abstract reasoning, suggesting that theory of mind and multitasking deficits following lesions to BA10 cannot be explained by a general worsening of executive function. In addition, we searched for correlations between performance and volume of damage within different subregions of BA10. Significant correlations were found between multitasking performance and volume of damage in right lateral BA10, and between theory of mind and total BA10 lesion volume. These findings stress the potential pivotal role of BA10 in higher order cognitive functions.

Executive functions in pathologic gamblers selected in an ecologic setting.

BackgroundRecent studies have reported deficits in measures of decision making in pathologic gamblers (PGs) suggesting an involvement of the prefrontal cortex in the pathophysiology of this disorder. As only 7% to 12% of PGs are thought to seek treatment, most of the studies have relied on few specifically selected groups of PGs recruited from psychiatric units who were undergoing or seeking treatment and therefore their results are poorly representative of the general PG population. MethodsThe present study compared decision making and executive functions among 11 PGs who were selected from an ecologic setting and 11 healthy controls. ResultsThe PG group selected fewer advantageous cards on a decision-making task, the Iowa Gambling Task, and made more commission errors on the Go-No Go task, a test of inhibitory control, compared with controls. ConclusionsThe impairments in decision making are similar to those previously reported in individuals with prefrontal lesions and treatment-seeking PGs. PGs also presented impairment in tasks of inhibitory control suggesting an involvement of the prefrontal cortex in the pathophysiology of pathologic gambling (PG). The deficits in decision making and inhibition of irrelevant information observed in this study may have distinct but additive effects upon the development of PG behavior.

The role of social cognition in moral judgment in frontotemporal dementia

Patients with behavioral variant frontotemporal dementia (bvFTD) exhibit a set of behavioral disturbances that have been strongly associated with involvement of the prefrontal cortex (PFC). Many such disturbances have been linked to impaired moral behavior, especially in regard to “personal” or “emotionally driven” moral dilemmatic judgment, which has been demonstrated to also depend on the integrity of the PFC. In this study, we administered a personal moral dilemma (the footbridge dilemma) and social cognition measures to patients with early bvFTD, who were also assessed with an extensive neuropsychological battery, including moral knowledge, cognitive and emotional empathy, and affective decision-making. BvFTD patients who would push a man off a footbridge (knowing this would kill him) to save the life of five workers who would have been otherwise killed by the train showed significantly lower scores on affective Theory of Mind (ToM) relative to those bvFTD patients who responded negatively. No significant differences were found on other sociodemographic, neuropsychological or social cognition variables. This study reveals that altered dilemmatic judgment may be related to impaired affective ToM, which has important clinical and theoretical implications.