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Clinical and cognitive diversity of psychotic states arising in late life (late paraphrenia).

This study aimed to explore the heterogeneity of paranoid psychosis with onset in late life by using cognitive factors in a centroid method of cluster analysis. Forty-seven subjects were allocated to two different clusters, the first with 24 (51.1%) and the second with 23 (48.9%) patients. Their cognitive attainment was evaluated against the performance of 33 elderly controls, all groups being matched for age, sex, and the numbers of years of education. Patients in cluster 2 showed a pattern of widespread cognitive impairment, which involved general measures of cognitive performance (MMSE, CAMCOG, WAIS-R verbal and performance scores), memory (digit and spatial span, delayed matching-to-sample, recognition memory for words and faces), and executive functions (verbal fluency, extra and intra-dimensional shift ability, spatial working memory, and planning). In contrast, patients in cluster 1 were only impaired on their extra-dimensional set shift and planning abilities, suggesting a more specific and restricted executive functioning deficit. We also analysed the impact that the use of antipsychotic medication could have had on patients' cognitive performance, which was shown to be negligible. In addition, there was no difference between the clusters with regard to the number of patients using neuroleptics, suggesting that the medication was unlikely to have introduced a performance bias in the two patient clusters. The validity of the subdivision of these patients into two separate groups was further supported by other clinical findings. Patients in cluster 1 exhibited more severe psychotic symptoms, as measured by the SAPS, than their counterparts in cluster 2, and were also more likely to display first-rank symptoms of Schneider. Conversely, cluster 2 membership was strongly associated with the presence of neurological signs and negative symptoms. We suggest that psychotic states arising in late life are a heterogeneous condition that may be best divided in two: 'type A', including patients with a wide range of psychotic symptoms, mild increase in the frequency of neurological signs, and cognitive deficits restricted to executive functions, and 'type B', which includes patients with less complex psychotic symptoms associated with a marked increase in the frequency of neurological signs and generalized cognitive impairment. The basis for this subdivision and the prospect for future studies are discussed.

Aged

Cognitive outcome after aneurysm rupture: relationship to aneurysm site and perioperative complications.

We evaluated cognitive outcome in a group of 37 patients who had undergone surgery for rupture and repair of a single intracranial aneurysm at least 6 months previously. We compared outcome--assessed by tests of intelligence, attention, executive functions sensitive to frontal lobe lesions, memory, neglect, and mood, as well as by a specially devised questionnaire--between a group of 20 patients who had aneurysms of the anterior communicating artery and 17 patients who had aneurysms located on other branches of the internal carotid artery. There were no differences in cognitive outcome between patients with anterior communicating artery aneurysms and those with aneurysms on other branches of the internal carotid artery. The patient group as a whole, however, showed impairment in executive functions and some aspects of memory in comparison with normative data. Overall, 65% of the patients were impaired in at least one cognitive domain, with 19% showing executive impairments alone, 14% showing memory impairments alone, and 32% showing deficits in both domains. Cognitive outcome was most strongly predicted by postoperative neurologic events, although clipping of an anterior cerebral artery was associated with a higher impairment rating on a symptom profile completed by patients' relatives, and although preoperative rebleeding of aneurysms predicted impairment of executive function.

Adult

Disorders in executive control functions among aphasic and other brain-damaged patients.

Four experimental procedures for assessing disorders of executive control (Nonverbal Continuous Performance, Graphic Pattern Generation, Sequence Generation Test, and Tower of Hanoi) were administered to 22 left-brain-damaged aphasic patients, 19 right-brain-damaged nonaphasic patients, and 49 healthy controls. Aphasic patients with frontal-lobe lesions were significantly more impaired on these tasks than aphasics with retrorolandic or mixed lesions in the left hemisphere. Patients with right-hemisphere lesions, especially those with frontal-lobe lesions, showed even greater impairments on these visual/spatial tasks. The results suggest that aphasics' impairments in executive control are independent of their linguistic and visuospatial deficits and are specific to lesions in left frontal and prefrontal regions. The clinical utility of the experimental procedures is discussed.

Adult

Prenatal exposure to marihuana and tobacco during infancy, early and middle childhood: effects and an attempt at synthesis.

Both marihuana and cigarettes appear implicated, in a differential fashion, in the neurobehaviour of infants and children born to women who used these substances during pregnancy. In a low-risk upper middle class sample, marihuana use was associated, in the newborn, with mild withdrawal symptoms and some autonomic disruption of nervous system state regulation. However, between 6 months and 3 years of age no behavioural consequences of marihuana exposure (once confounding factors were controlled) were noted. At four years of age, although global tests of intelligence did not differentiate exposed from non-marihuana exposed children, verbal ability and memory were associated with in utero marihuana exposure. At five and six years of age these general areas were also noted to be associated with maternal cannabis use as was sustained attention. These areas of neurobehavior that appear affected by marihuana exposure during fetal development are ones that are consistent with the cognitive construct of 'executive functioning' which is thought to be a marker of prefrontal lobe functioning. Consistent with the observations derived from these children is that prefrontal functioning may not be apparent until approximately four years of age and that executive functioning is disassociated from measures of global intelligence. Exposure to cigarettes during pregnancy appears to be associated with neurobehavioural deficits in the auditory domain. In the newborn this is manifested by decreased responsivity to sound and altered auditory habituation. Between the ages of one and 11 years the performance on auditory related tasks (verbal memory, language, auditory processing) were consistently the domains that differentiated the cigarette exposed from the non exposed children. The possible role of the cholinergic mediated efferent auditory system is discussed. Also associated with in utero exposure to cigarettes were general cognitive performance and parental reports and objectively derived measures of impulsivity. The striking degree of consistency over the years lends strength to the interpretation that the observations in childhood have, at least as their partial etiology, the prenatal exposure to cigarettes. However, in interpreting the evidence presented it must be recognized that the alterations in the child's behaviour may well affect the parenting behaviour. This potential transactional interaction must remain an integral part of drawing conclusions about both marihuana and cigarette's effects.

Behavior

Asperger's syndrome: evidence of an empirical distinction from high-functioning autism.

This study compared the neuropsychological profiles of individuals with high-functioning autism (HFA) and Asperger's syndrome (AS). In comparison with matched controls, both groups were impaired on executive function tests. Only the HFA group demonstrated deficits in theory of mind and verbal memory, performing more poorly than both controls and AS subjects. These results suggest that: (1) HFA and AS are empirically distinguishable on measures independent of diagnostic criteria, and (2) impairment on theory of mind measures is not universally found among individuals with autistic spectrum conditions. The primacy of executive function and theory of mind deficits to autism is discussed.

Autistic Disorder

Cognitive deficits in patients with small cell lung cancer before and after chemotherapy.

We conducted a prospective study of cognitive function in patients with small cell lung cancer (SCLC). A previous study had shown SCLC patients to have deficits in memory, frontal lobe executive functioning, and motor skills before they received prophylactic cranial irradiation (PCI). This study was performed to determine whether these deficits were related to chemoradiation treatment. We evaluated two groups of patients: one newly diagnosed and untreated, the other post-chemoradiation and before PCI. Strict eligibility criteria were used to minimize any preexisting factors that might influence cognitive functioning. Results showed that patients with SCLC have cognitive deficits before receiving chemoradiation, specifically on tests of verbal memory, frontal lobe executive functions, and motor coordination. There was no difference between the treated and untreated patients on any test. Etiologic considerations currently under study include paraneoplastic phenomena.

Adolescent

Behavioural changes after closed head injury. A neuropsychological issue.

The long-term behavioural consequences of moderate to severe closed head injury (CHI) have been examined within a neuropsychological framework. It is argued that neuropsychological assessment must be considered if the behavioural sequelae of a brain injury are to be fully appreciated and assessment and rehabilitation modules appropriately formulated. Functioning of the frontal lobes is emphasised because this is the area most at risk when a head injury occurs. The meaning of 'executive functions' is examined, and the behavioural and rehabilitation implications of an impaired 'executor' are discussed. It is demonstrated that traditional individual and family-based psychotherapeutic techniques are inappropriate for people with impaired executive functions.

Behavior

Neuropsychological changes in a prospectively followed cohort of homosexual and bisexual men with and without HIV infection.

We evaluated neuropsychological test performance of 168 homosexual and bisexual men with and without human immunodeficiency virus (HIV) infection (113 HIV+ subjects and 55 HIV- controls) over 4.5 years of semiannual follow-up. Analyses of the longitudinal data were performed by applying generalized estimating equations (GEEs) to regression analyses with repeated measures. Compared with the HIV- men, the HIV+ subjects performed more poorly on memory testing. Performance on all tests tended to improve over time, but this improvement was attenuated or eliminated in the HIV+ group for tests of language and attention. Within the HIV+ subjects, improvement over time in tests of memory, executive function, language, and attention was attenuated or eliminated in patients with lower CD4 levels; more advanced HIV disease was associated with poorer memory and executive function and with attenuated or reduced learning effects for memory, motor speed, and language tests. Clinically significant neurologic findings were associated with worse memory and orientation and with attenuated or reversed learning effects for memory, language, and attention tests. There were 33 deaths in the HIV+ group. In the men who died, there was more rapid decline in executive, language, and attentional test performance. These observations remained significant after controlling for HIV disease severity. We conclude that HIV infecting the CNS results in progressive cognitive change that is closely associated with neurologic findings. In addition, our findings suggest a relation between more rapid cognitive progression and death.

Adult

Developmental impact of frontal lobe injury in middle childhood.

Executive function of frontal lobe systems, like intelligent behavior, appears to demonstrate two major features: it is adaptive and goal-directed. Disruption of executive function following injury to the frontal lobes in childhood might be predicted to impact the trajectory of normal cognitive, behavioral, and social development. Case studies of two children injured at different ages showed the primary developmental impact to involve the behavioral and social realms. While cognitive development may be suspected to also be considerably influenced, assessment of changes in cognitive abilities by traditional psychometric means was found to be problematic. Psychometric changes were found to occur over a prolonged period of time, emphasizing the importance of documenting observations and chronicling postinjury events.

Brain Injuries

Neuropsychological and neuroanatomical correlates of confabulation.

In the present exploratory investigation we report nine confabulatory patients of comparable age, education, and general level of intelligence in the acute epoch of recovery after rupture and clipping of ACoA aneurysms. Five of the nine cases had "spontaneous" confabulation, severe anterograde amnesia, markedly poor attentional and executive functions, and denial of illness. These patients all had multiple lesions that involved basal forebrain, ventral frontal lobe, and striatum. The other four patients manifested only "momentary" or "provoked" confabulations. These patients also had severe anterograde amnesia but showed relatively mild deficits in executive functions. These patients had lesions restricted to the basal forebrain except for one who had additional orbital frontal damage. Analysis of these two groups of confabulatory patients suggests that there is a common profile of deficits and anatomic foundation associated with confabulation; "spontaneous" confabulation appears to require extensive, simultaneous disruption of medial basal forebrain and frontal cognitive systems resulting in profound executive and memory deficits, whereas more limited lesions to the basal forebrain or orbital frontal cortex will result in "transient" or "provoked" confabulatory responses and a more restricted profile of cognitive deficits.

Adult

Planning disorder after closed head injury: a case study.

Disturbances of executive functioning after traumatic brain injury represent significant obstacles to social and vocational recovery and may require specific remedial intervention. We report the treatment of a client with impaired planning ability and poor self-control after closed head injury. Intervention consisted of a self-instructional procedure that required him to verbalize a plan of behavior before and during execution of the training task and gradually faded overt verbalization. There was systematic reduction of off-task behaviors and problem-solving errors over the eight weeks of training. Pre- and postmeasures showed significant changes consistent with increased planning ability. Self-control ratings of everyday behaviors improved with explicit training to promote generalization. Training of plan-ahead and self-verbalization strategies appears effective for remediation of executive functioning after traumatic brain injury. Generalization to real-life situations can be observed with extended training.

Adult

Neurobehavioral characteristics of CGG amplification status in fragile X females.

Neurobehavioral correlates of CGG amplification were studied in 17 nonretarded adult female carriers of fragile X syndrome. The results revealed a significant relationship between IQ and the number of CGG repeats in the 5' untranslated region of the FMR1 gene. Women with a full mutation (> 200 CGG repeats) scored below average in IQ, visual-spatial perception, visual-spatial organization, and executive function. There were no differences in fine motor dexterity or memory as a function of CGG amplification status. A history of major depressive disorder was identified in 71% of the sample, but incidence of depression was not associated with the degree of CGG amplification. Schizotypal features were noted in 18%. No intellectual or neuropsychological deficit was found in women with a premutation (< 200 CGG repeats). Decrements in IQ, visual-spatial perception, and executive function appear to arise as a consequence of the CGG amplification.

Adult

Cognitive features of psychotic states arising in late life (late paraphrenia).

The cognitive performance of 47 elderly psychotic patients with onset of symptoms in late life (late paraphrenia) was compared to that of 33 controls matched for age, sex, ethnic origin, number of years of education, and pre-morbid IQ as measured by the NART. Neuropsychological indices of general cognitive functioning (MMSE, CAMCOG, WAIS-R verbal and performance scores) showed that patients were performing the tasks at a significantly lower level than controls. Patients also showed a trend to have a lower span capacity than controls, particularly at the spatial span subtest. There was no obvious impairment of learning as measured by the digit and spatial recurring span tasks nor of simultaneous matching-to-sample ability. However, patients' performance on a delayed-matching-to-sample procedure was significantly worse than that of controls. In addition, patients performed worse than controls on the Recognition Memory Test for Faces, but not for Words. Finally, the performance of patients on tests assessing executive functioning (Verbal Fluency Test, Computerized Extra and Intra-Dimensional Shift Task, Computerized Spatial Working Memory Task, and Computerized Tower of London Task) was consistently worse than that of controls. These results suggest that psychotic states arising in late life are predominantly associated with a decline on measures of general cognitive ability and executive functioning. The neuropsychological meaning of these findings is discussed in the light of cognitive models of psychotic symptoms, as well as of schizophrenia and dementia research. We concluded that the lack of a clear pattern of impairment among these patients may be the result of their clinical and cognitive diversity.

Aged

Effect of instructional cues on schizophrenic patients' performance on the Wisconsin Card Sorting Test.

OBJECTIVE: Schizophrenic patients are particularly deficient on measures of executive functioning, notably the Wisconsin Card Sorting Test. This study was conducted to determine the efficacy of a cuing strategy in facilitating performance on this cognitive measure of the integrity of prefrontal brain structures and functioning. METHOD: Twenty-four schizophrenic inpatients and 24 demographically matched inpatients with mood disorders were administered the Wisconsin Card Sorting Test either with instructional cues at the beginning of the task or with the standard administration procedure. RESULTS: There was a significant benefit of cues for the patients with affective disorders as well as for the schizophrenic patients. The schizophrenic subjects in the uncued condition maintained poor but stable performance throughout the course of the task. CONCLUSIONS: The study suggests that the deficit in executive functioning of schizophrenic patients may lie in the formation of concepts, not in their application.

Adolescent

Synaptic Mitochondrial Oxidative Stress Contributes to Individual Variability in Age-Related Cognitive Inflexibility in Mice.

Aging is associated with impairments in cognitive flexibility, a key executive function supported by the medial prefrontal cortex (mPFC), yet the biological mechanisms underlying individual variability in age-related decline remain poorly understood. Here we investigated behavioral, ultrastructural, and proteomic correlates of cognitive inflexibility in mice across aging. Using a touchscreen-based attentional set-shifting task, we observed substantial individual variability in cognitive inflexibility among aged C57BL/6J mice. Volume electron microscopy of the mPFC revealed age-related reductions in synaptic density, but these structural changes did not correlate with cognitive performance. Instead, the proportion of synapses containing presynaptic mitochondria was inversely associated with cognitive flexibility in aged mice. To identify molecular correlates, we performed proteomic profiling of mPFC whole tissue and synaptosome fractions. Proteins associated with individual variability in cognitive inflexibility were largely distinct from those associated with chronological aging. Notably, synaptosomal proteins negatively correlated with cognitive performance were strongly enriched for mitochondrial pathways, including oxidative phosphorylation, mitochondrial translation, and the tricarboxylic acid cycle. Consistent with these findings, the mitochondria-targeted antioxidant MitoQ improved attentional set-shifting performance in aged mice without affecting initial learning. Proteomic analyses revealed that MitoQ reduced the abundance of synaptosomal mitochondrial proteins, particularly those involved in mitochondrial apoptotic signaling. Together, these results suggest that synaptic mitochondrial oxidative stress in the mPFC contributes to individual vulnerability to cognitive inflexibility. Targeting synaptic mitochondrial oxidative stress may therefore represent a promising strategy to preserve executive function during aging.

Animals

Free-water: A promising structural biomarker for cognitive decline in aging and mild cognitive impairment.

Diffusion MRI derived free-water (FW) metrics show promise in predicting cognitive impairment and decline in aging and Alzheimer's disease (AD). FW is sensitive to subtle changes in brain microstructure, so it is possible these measures may be more sensitive than traditional structural neuroimaging biomarkers. In this study, we examined the associations among FW metrics (measured in the hippocampus and two AD signature meta-ROIs) with cognitive performance, and compared FW findings to those from more traditional neuroimaging biomarkers of AD. We leveraged data from a longitudinal cohort (nparticipants = 296, nobservations = 870, age at baseline: 73 &#xb1; 7 years, 40% mild cognitive impairment [MCI]) of older adults who underwent serial neuropsychological assessment (episodic memory, information processing speed, executive function, language, and visuospatial skills) and brain MRI over a maximum of four time points, including baseline (n = 284), 18-month (n = 246), 3-year (n = 215), and 5-year (n = 125) visits. The mean follow-up period was 2.8 &#xb1; 1.3 years. Structural MRI was used to quantify hippocampal volume, in addition to Schwarz and McEvoy AD Signatures. FW and FW-corrected fractional anisotropy (FAFWcorr) were quantified in the hippocampus (hippocampal FW) and the AD signature areas (SchwarzFW, McEvoyFW) from diffusion-weighted (dMRI) images using bi-tensor modeling (FW elimination and mapping method). Linear regression assessed the association of each biomarker with baseline cognitive performance. Additionally, linear mixed-effects regression assessed the association between baseline biomarker values and longitudinal cognitive performance. A subsequent competitive model analysis was conducted on both baseline and longitudinal data to determine how much additional variance in cognitive performance was explained by each biomarker compared to the covariate only model, which included age, sex, race/ethnicity, apolipoprotein-&#x3b5;4 status, cognitive status, and modified Framingham Stroke Risk Profile scores. All analyses were corrected for multiple comparisons using an FDR procedure. Cross-sectional results indicate that hippocampal volume, hippocampal FW, Schwarz and McEvoy AD Signatures, and the SchwarzFW and McEvoyFW metrics are all significantly associated with memory performance. Baseline competitive model analyses showed that the McEvoy AD Signature and SchwarzFW explain the most unique variance beyond covariates for memory (&#x394;Radj 2 = 3.47 &#xb1; 1.65%) and executive function (&#x394;Radj 2 = 2.43 &#xb1; 1.63%), respectively. Longitudinal models revealed that hippocampal FW explained substantial unique variance for memory performance (&#x394;Radj 2 = 8.13 &#xb1; 1.25%), and outperformed all other biomarkers examined in predicting memory decline (pFDR = 1.95 x 10-11). This study shows that hippocampal FW is a sensitive biomarker for cognitive impairment and decline, and provides strong evidence for further exploration of this measure in aging and AD.

Alzheimer&#x2019;s disease (AD)

[Deficits in memory retrieval: an argument in favor of frontal subcortical dysfunction in depression].

UNLABELLED: While numerous studies have objective quantitative and qualitative deficits of memory in depressed patients, the mechanisms of these impairments are not well established. The study reported here was designed to assess encoding and retrieval processes in depression and to define the specific nature of memory failure associated with this disorder. METHODS: Ten inpatients with major depression responding to DSM III-R criteria and ten normal controls were included in this study. All subjects were assessed with a neuropsychological battery including: a) subtests of Weschsler memory scale (digit span, logical memory); b) verbal fluency (letter); c) two tasks assessing executive functions (cognitive estimate, Nelson's test); d) two explicit tasks of verbal learning (California Verbal Learning Test and Grober & Buschke's procedure) which measure memory performance in various conditions of encoding (incidental vs controlled) and of recollection (free recall, cued recall and recognition). Severity of depression was assessed with the MADRS and the Retardation Rating Scale for Depression. RESULTS: Although there was no difference between patients and controls on digit span and logical memory tasks, depressed patients exhibited a deficit in verbal learning with CVLT and Grober & Buschke's procedure. On California Verbal Learning Test, depressive subjects performed poorly in free recall and demonstrated poor consistency. Patients show free recall improvement across trials 1 or 5 and this learning effect didn't differ from controls. Score of patients and controls on cued recall and recognition were at the same level. Grober & Buschke's procedure confirmed these results. Despite a control of encoding processes during the initial presentation of the words, free recall measure revealed significant difference between groups. Like controls, patients recalled almost all items when semantic cues was provided and their recognition results showed a ceiling effect. Consistency indexes of free recall and cued recall differed significantly between groups. Verbal fluency and frontal tasks didn't allow to distinguish the depressive patients from controls. DISCUSSION: Depressive subjects exhibited a deficit in free recall and poor consistency while cued recall and recognition were normal. Patient's results in free recall are characterized by difficulties in planning and in maintaining retrieval strategies. These findings suggest that memory failure in depression could reflect an impairment in retrieval processes depending on executive functions controlled by the subcortical structures.

Adult

Performance and its measurement.

Performance involves numerous sub-functions, and cannot be treated as a unit. Several attempts have been made to separate functions impaired by different classes of drug: for example, high (monitoring) vs lower (performing) levels of function, early (perceptual) vs later (motor) functions, and strategic vs executive functions. The practical implications are that one cannot predict effects of a drug from a single performance test. One must either simulate the practical situation exactly, or use a battery of analytical tests to form a profile of effects. The latter is the policy urged in this paper.

Amphetamine