Further antinociceptive effects of myricitrin in chemical models of overt nociception in mice

Neurocognitive de?cits are recognized as core features of schizophrenia. The aim of this study was to compare the cognitive performance of antipsychotic, drug-naive patients with first-episode schizophrenia (FES patients) to their healthy siblings and to healthy controls from the Han Chinese population for exploring potential endophenotypes for the early detection of schizophrenia. A battery of cognitive assessment tools was used to measure seven cognitive domains in matched groups consisting of 56 subjects each. Cognitive tests included the grooved pegboard test (GPT), the category fluency test (CFT), the trail making test A (TMT-A), the Wechsler memory scale-III spatial span test (WMS-III SST), the Hopkins verbal learning test-revised (HVLT-R), the brief visuospatial memory test-revised (BVMT-R), the paced auditory serial addition test (PASAT), and the Wisconsin card sorting test-64 cards version (WCST-64). The performances of FEP patients were inferior to normal controls on all neuropsychological tests, while siblings were lower than healthy controls in many of the same tasks. Patients’ performances were lower than siblings’ on all tests except for the CFT, the WMS-III SST backward test, and four subtests of the WCST-64. Our data suggest that FEP patients exhibited pronounced impairment of fine motor skills, speed of processing, attention, verbal memory, visual memory, and executive function, while siblings exhibited deficits intermediate between those of schizophrenic patients and the control group. Semantic fluency function and executive function may be potential endophenotypes for the early diagnosis of schizophrenia.     

Memory performance in healthy elderly without Alzheimer's disease: effects of time and apolipoprotein-E.

Transgenic mice expressing human APOE-epsilon4 develop an age-dependent decline in memory without pathological features of Alzheimer's disease (AD). This implicates APOE in the maintenance of memory during normal senescence, but parallel human studies are limited because longitudinal investigations of memory usually do not exclude patients with AD or "questionable" AD (QD). The current study examined the effect of APOE on cognitive function over time in elderly without dementia. We hypothesized that, compared to other APOE alleles memory decline even in healthy elderly would be greater among those with an APOE-epsilon4. The results of neuropsychological tests, grouped into domains of memory, language and visuospatial/cognitive function by factor analysis, were examined at three intervals over a seven-year period in 563 healthy elderly without AD or QD using generalized estimating equations. Memory performance declined over time, while scores on the visuospatial/cognitive and language factors did not change. Increased age was associated with lower scores, and higher education with higher scores on all factors at each interval. No APOE allele was associated with performance on a specific cognitive factor at any interval, but the presence of an APOE-epsilon4 allele was associated with a more rapid decline in the memory factor over the follow-up period. The effect was most pronounced among individuals with less than 10 years of formal education. There was no similar time-dependent relationship between APOE-epsilon4 and the language or visuospatial/cognitive factors. Transgenic mice and elderly humans without AD or QD expressing APOE-epsilon4 show a decline in memory performance over time. These observations provide evidence for an APOE-specific effect on memory during senescence.     

Cognitive profiles of mild cognitive impairment with and without vascular disease

This study examined whether the cognitive profile of subjects with mild cognitive impairment (MCI) with vascular disease differs from that of MCI subjects with no vascular disease. Consecutive MCI subjects with vascular disease (n=60) and matched MCI subjects with no vascular disease (n=60) were included in the study and were compared with healthy control subjects (n=60). The neuropsychological assessment comprised tests of speed and attention, episodic memory, visuospatial function, language, and executive function. Control subjects performed significantly better than did both MCI groups on the neuropsychological battery. MCI subjects with no vascular disease performed better overall than did MCI subjects with vascular disease, most clearly on tests of speed and attention, visuospatial function, and executive function. MCI subjects with and without vascular disease exhibited differences, both in terms of overall performance and of cognitive profiles. These differences can be largely explained by deficits in speed and attention and in executive function of the MCI subjects with vascular disease.     

The neuropsychology of adult obsessive–compulsive disorder: A meta-analysis

A vast and heterogeneous body of literature on the neuropsychology of obsessive–compulsive disorder (OCD) has accumulated in recent decades, yielding inconsistent results. In an attempt to quantitatively summarize the literature, we conducted a meta-analysis of 115 studies (including 3452 patients), comparing adult OCD patients with healthy controls on tests of 10 neuropsychological domains. Across studies, medium mean effect sizes were found for all executive function subdomains, processing speed, and sustained attention. Small effect sizes were found for visuospatial abilities and working memory. A large effect size was found for non-verbal memory whereas a small effect size was found for verbal memory, where only the former was found to be associated with impairments in executive functions. Moderators of effect sizes were also investigated. Results are discussed in terms of their clinical significance as well as their implications for current neurobiological models of OCD and methodological caveats.     

Computerized cognitive testing in patients with type I Gaucher disease: effects of enzyme replacement and substrate reduction.

PURPOSE: Because of concern for drug-induced cognitive dysfunction during clinical trials using substrate reduction therapy (miglustat) in type 1 Gaucher disease and because it has been suggested that some patients with type 1 Gaucher disease may develop neurocognitive impairment as part of the natural history, two different batteries of neuropsychological tests were devised to examine these issues. Using these tests, cognitive function was assessed in patients treated with miglustat, in patients receiving enzyme replacement (standard care for symptomatic patients), and in untreated (milder) patients. METHODS: For this study, 55/60 patients exposed to miglustat in Israel participated in psychologist-administered testing; 36/55 participated in computerized testing. Of these, 31 enzyme-treated patients and 22 untreated patients participated in the psychologist-administered testing, and 15 enzyme-treated patients and 18 untreated patients participated in computerized testing. The psychologist-administered battery consisted of 18 standard neuropsychological subtests specific to executive and visuospatial functioning. The computerized battery (Mindstreams, NeuroTrax Corp., New York, NY) consisted of 10 subtests tapping multiple cognitive domains. Between-group analyses for each modality compared cognitive performance. RESULTS: In the psychologist-administered testing, patients exposed to miglustat performed significantly less well than the other groups in 5/18 subtests. On the computerized tests, all patients performed comparably to normal controls. Scores in patients exposed to miglustat were higher than in untreated patients, particularly in visuospatial function, whereas enzyme-treated patients performed less well. However, with the exception of visuospatial function, these results were not statistically significant. CONCLUSIONS: It is unclear why different testing methods yielded discordant results. Any dysfunction suggested by the current study is apparently subtle and of doubtful clinical relevance given that cognitive status did not interfere with patients' daily intellectual function. The computerized battery has methodological advantages (e.g., language options, objectivity, brevity, and ease of use) that make it well-suited for longitudinal studies, for long-term surveillance of substrate reduction therapy as well as for comparisons with other lysosomal storage disorders and other chronic diseases. These preliminary findings should allay fears of cognitive dysfunction due to short-term miglustat therapy.     

The cognitive neuropsychology of depression in the elderly

BACKGROUND: The cognitive impairment of older depressed patients with late- as opposed to early-onset illness may show important differences, in that patients with early onset may suffer predominantly from impaired episodic memory, and those with late onset mainly from reductions of executive function and processing speed. METHOD: We searched Medline and EMBASE as well as individual papers' reference lists for relevant publications, recording comparisons in neuropsychological test results between early-onset depression (EOD), late-onset depression (LOD) and healthy volunteers. Effect sizes are presented for cognitive domains, such as executive function, processing speed, episodic memory, semantic memory and mental state examination. RESULTS: Patients with LOD showed greater reductions in processing speed and executive function than patients with EOD and controls. Both patient groups showed reduced function in all domains, except mental state, compared with controls.CONCLUSION: Pronounced executive deficits are typical of the late-onset patients described in published studies, while episodic memory impairment is not specific to early-onset illness. Possible reasons and confounders are discussed.     

Regionally specific atrophy of the corpus callosum in AD, MCI and cognitive complaints

The goal of the present study was to determine if there are global or regionally specific decreases in callosal area in early Alzheimer's disease (AD) and mild cognitive impairment (MCI). In addition, this study examined the corpus callosum of healthy older adults who have subjective cognitive complaints (CC) but perform within normal limits on neuropsychological tests. We used a semi-automated procedure to examine the total and regional areas of the corpus callosum in 22 patients with early AD, 28 patients with amnestic MCI, 28 healthy older adults with cognitive complaints, and 50 demographically matched healthy controls (HC). The AD, MCI, and CC groups all showed a significant reduction of the posterior region (isthmus and splenium) relative to healthy controls. The AD group also had a significantly smaller overall callosum than the controls. The demonstration of callosal atrophy in older adults with cognitive complaints suggests that callosal changes occur very early in the dementing process, and that these earliest changes may be too subtle for detection by neuropsychological assessments, including memory tests.     

Neuropsychological differences among empirically derived clinical subtypes of schizophrenia.

Neuropsychological profile differences between empirically derived clinical subtypes of schizophrenia were examined. Two hundred five patients and 209 demographically matched controls were administered a neuropsychological battery examining 8 domains. Subtypes included negative, disorganized, paranoid, Schneiderian, and mild. All subtypes displayed a neuropsychological profile of generalized impairment with greater deficits in learning, memory, and attention. Results were suggestive of diffuse cognitive dysfunction in schizophrenia with more severe deficits in learning and memory relative to executive skills. This pattern of greater learning and memory impairment was pronounced for disorganized patients. In contrast, paranoid patients outperformed disorganized and negative patients in several domains. These findings reflect bilateral frontal-temporal dysfunction, particularly in disorganized and negative patients. Subtype differences highlight the importance of conceptualizing schizophrenia as a multifocal disorder.     

Neuropsychological performance in adult attention-deficit hyperactivity disorder: meta-analysis of empirical data.

Attention-deficit hyperactivity disorder (ADHD) is increasingly recognized not only in children but also in adults. Neuropsychological tests are important tools to quantify the attentional and/or cognitive deficits of patients compared to controls. The present meta-analysis integrates 24 empirical studies reporting results of at least one of 50 standard neuropsychological tests comparing adult ADHD patients with controls. The 50 tests were categorized into the following 10 functional domains: verbal ability, figural problem solving, abstract problem solving, executive function, fluency, simple attention, sustained attention, focused attention, verbal memory, figural memory. For each domain a pooled effect size d' was calculated. Complex attention variables and verbal memory discriminated best between ADHD patients and controls. Effect sizes for these domains were homogeneous and of moderate size (d' between 0.5 and 0.6). In contrast to results reported in children, executive functions were not generally reduced in adult ADHD patients.     

Longitudinal Analysis of the Effects of the Aging Process on Neuropsychological Test Performance in the Healthy Young-Old and Oldest-Old

A sample of 33 young-old (ages 65 to 74) and 20 oldest-old (ages 84 to 93) healthy elderly without dementia were assessed with neuropsychological tests annually over a 4-year period to examine longitudinal changes in cognitive functioning. Significant age-group differences existed at baseline in participants' performances on tests of immediate memory and visuospatial skills. There were no age-group differences in the rate of change over the 4-year interval on any neuropsychological tests. Within each age-group, the amount of change over time was minimal for most tests though some practice effects were apparent, and on some tests mild decline was observed. Results suggest that healthy old adults, including the oldest-old, do not experience measurable declines in cognitive functioning over a 4-year period.     

Obesity enhances verbal memory in postmenopausal women with Down syndrome

Several lines of evidence suggest that the loss of estrogen after menopause may play a role in cognitive declines associated with Alzheimer's disease (AD). In postmenopausal women, the principal source of estrogen is estrone, which is influenced by body mass index (BMI). Increased BMI in postmenopausal women is associated with higher levels of serum estradiol and estrone. We hypothesized that obesity could have a beneficial effect on cognition with advancing age. We compared the performance of healthy nondemented obese and non-obese women with Down syndrome (DS) on a broad spectrum of cognitive tests. Estrone levels were 66.9% higher in obese than in non-obese postmenopausal women, and 136% higher in obese than in non-obese premenopausal women. Obese postmenopausal women performed significantly better than non-obese women on measures of verbal memory and on an omnibus test of neuropsychological function, but did not differ significantly in verbal fluency, language, praxis or visuospatial functioning. Among premenopausal women, there was no difference in cognitive function between obese and non-obese women. Our results support the hypothesis that higher endogenous estrogen levels after menopause are associated with better performance on verbal memory.     

Specific Neuropsychological Deficits in Schizophrenic Patients with Preserved Intellectual Function

Although a wide range of cognitive deficits have been demonstrated in schizophrenia, it is not clear whether specific deficits stand out from general intellectual decline. Separate cases have been made for selective impairments in mnemonic and in executive function but these remain unconfirmed. A common problem in studies of schizophrenia is heterogeneity of deficits and Shallice, Burgess, and Frith (1991) have addressed this by using a single case study approach. The present study used the CANTAB battery of neuropsychological tests to examine cognitive performance in a small group of schizophrenic patients with preserved intellectual function. This test battery allows a componential analysis of performance, and its neurological validation may enable specific neurobiological hypotheses to be addressed. Twelve schizophrenic patients with current IQ greater than 90 and within 10 points of premorbid IQ were assessed on tests of visuospatial memory, spatial working memory, planning, and attentional set-shifting. Their performance was compared to that of 12 matched controls. The patient group, as a whole, was impaired on all tasks but the pattern of impairment varied across individuals. Consistently, severe deficits were seen on tests of delayed matching to sample and attentional set-shifting. These deficits are compared to those seen in patients with unipolar depression, who showed similar deficits in delayed matching to sample but not set-shifting, and are considered in terms of common cognitive mechanisms and possible neural substrates.     

Longitudinal analysis of the effects of the aging process on neuropsychological test performance in the healthy young-old and oldest-old

A sample of 33 young-old (ages 65 to 74) and 20 oldest-old (ages 84 to 93) healthy elderly without dementia were assessed with neuropsychological tests annually over a 4-year period to examine longitudinal changes in cognitive functioning. Significant age-group differences existed at baseline in participants' performances on tests of immediate memory and visuospatial skills. There were no age-group differences in the rate of change over the 4-year interval on any neuropsychological tests. Within each age-group, the amount of change over time was minimal for most tests though some practice effects were apparent, and on some tests mild decline was observed. Results suggest that healthy old adults, including the oldest-old, do not experience measurable declines in cognitive functioning over a 4-year period.     

Do cognitive complaints in euthymic bipolar patients reflect objective cognitive impairment?

BACKGROUND: In clinical practice, bipolar patients complain of cognitive deficits such as attentional or memory disturbances. The main aim of this study was to determine whether subjective cognitive complaints were associated with objective neuropsychological impairments. METHOD: Sixty euthymic bipolar patients were assessed through a neuropsychological battery. A structured clinical interview was used to determine subjective cognitive complaints in patients. Thirty healthy controls were also included in the study in order to compare the neuropsychological performance among groups. RESULTS: Bipolar patients with a higher number of episodes, especially the number of mixed episodes, longer duration of the illness and the onset of the illness at an earlier age showed more subjective complaints. Furthermore, bipolar patients with subjective complaints showed lower scores in several cognitive measures related to attention, memory and executive function compared with the control group. Nevertheless, patients without complaints also performed less well than controls in some neuropsychological measures. CONCLUSION: Bipolar patients who were aware of cognitive deficits were more chronic, had presented more previous episodes, especially mixed type, and their illness had started at an earlier age compared with patients who did not complain about cognitive problems. Moreover, patients with good cognitive insight also had a poorer social and occupational functioning as well as a poorer neuropsychological performance. However, the bipolar group without complaints also obtained lower scores in several tests compared with healthy controls. Cognitive status of bipolar patients should be routinely assessed, regardless of the patients awareness about their cognitive deficits.     

Decreased working memory and processing speed mediate cognitive impairment in geriatric depression

BACKGROUND: While neuropsychological dysfunction is common in geriatric depression, not all aspects of cognition are equally affected. It has been suggested that depressed patients are impaired only in tasks that make heavy demands on processing resources and that a resource decrement therefore underlies the neuropsychological decrements seen in geriatric depression. The present study examined whether processing resources in the form of working memory and information processing speed are decreased in depression and whether a decrease in these resources actually mediates neuropsychological impairment. METHODS: Measures of processing resources were administered to elderly depressed patients prior to treatment and to age-matched controls. Patients whose depression remitted were retested as were the controls. Subjects also received neuropsychological tests of episodic memory and visuospatial performance. RESULTS: Depressed patients performed significantly worse on measures of both processing speed and working memory. While performance on these measures improved in patients whose depression remitted, the amount of improvement was no greater than that seen in the controls with repeat testing. Hierarchical regression analyses showed that depression explained a significant amount of variance on the neuropsychological tasks. However, if the variance associated with processing resources was removed first, depression no longer accounted for a significant amount of neuropsychological variance. CONCLUSIONS: Processing resources are decreased in elderly depressed patients and this decrease in resources appears to mediate impairments in several areas of neuropsychological functioning including episodic memory and visuospatial performance. The resource decrement persists after remission of the depression and thus may be a trait marker of geriatric depression.     

The Penn Conditional Exclusion Test: a new measure of executive-function with alternate forms of repeat administration.

Studies of change in neuropsychological function over time in both healthy and diseased populations have been hindered by the absence of alternate forms of most commonly used neuropsychological tests. The Penn Conditional Exclusion Test (PCET) was developed as a new cognitive instrument to assess "executive" functioning with four alternate forms. In Study 1, the PCET was administered in counterbalanced order to 80 healthy young adults to establish equivalent test difficulty. Results revealed that the four versions were related on categories achieved, total number of errors and total number of trials. In Study 2, the PCET was administered to 25 healthy adults of a wide age range with a battery of computerized neuropsychological tests to assess construct validity. Convergent validity was confirmed by positive correlations between the PCET and a measure of abstraction. Divergent validity was established through low, nonsignificant correlations between the PCET and measures of facial emotion recognition, word and face memory, visuospatial function, and verbal reasoning.     

Self- and informant reports of executive function on the BRIEF-A in MCI and older adults with cognitive complaints.

Amnestic mild cognitive impairment (MCI) is characterized by impaired episodic memory, although subtle executive problems have been noted on neuropsychological tests. Recent research also has described a group of healthy, non-depressed older adults with significant cognitive complaints (CC) but normal performance on neuropsychological testing. These individuals show structural and functional brain changes intermediate between those seen in MCI and healthy older adults without such complaints (HC). We evaluated executive functions in MCI and CC using the Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A), a newly developed self- and informant report questionnaire in 29 patients with amnestic MCI, 28 CCs, and 30 demographically matched HCs. MCI and CC participants reported significant difficulties with selective aspects of executive functioning relative to HCs despite clinically normal performance on neuropsychological tests of this cognitive domain. Scores were generally in the pattern of MCI>CC>HC, and findings were most pronounced for working memory. Additionally, MCI and CC participants were more likely than their informants to report clinically meaningful executive problems, though informants identified a similar pattern of difficulty overall. Results failed to reveal strong relations between the BRIEF-A and standardized neuropsychological tests of executive function. Overall findings indicate that the BRIEF-A is sensitive to subtle executive changes in MCI and CC and suggest the need for research to determine if executive complaints are predictive of clinical course.     

Comparative cognitive profiles of obsessive-compulsive disorder and schizophrenia

A body of neuropsychological research revealed cognitive impairments in patients suffering from obsessive-compulsive disorder (OCD). Only few investigations addressed the question of how specific these impairments are. The present study compared the performances of 19 subjects with OCD to 19 subjects with schizophrenia and 19 healthy controls on neuropsychological tasks across the main cognitive domains (memory, attention, visual spatial and executive functioning). For purposes of data-reduction, single test measures of the test battery applied were aggregated into eight cognitive domain scores. Contrary to our expectation we found comparable performance profiles of obsessive-compulsive (OC) and schizophrenia subjects across domains with impairments primarily affecting simple attentional skills and memory skills. However, deficits of subjects with schizophrenia were greater in magnitude than those of subjects with OCD on all domains assessed. Elevated depression scores exerted a relevant impact on performance deficits in the OC but not in the schizophrenia sample.     

Memory and executive impairment in schizophrenia: comparison with frontal and temporal brain damage

BACKGROUND: Although poor neuropsychological test performance is well documented in schizophrenia, how closely it resembles that seen in patients with brain damage in terms of cognitive failures in daily life and stability over time has been little studied. METHOD: Thirty patients with chronic schizophrenia, 24 patients with frontal or temporal brain damage and 30 healthy controls were given a battery of memory and executive tests. Carers of the two patient groups also completed questionnaires rating memory and executive failures in daily life. Testing was repeated 6 weeks later. RESULTS: The schizophrenia and the brain-damaged patients were significantly impaired on most, but not all tests. The degree of carer-rated memory or executive failure was similar in the two groups, but the schizophrenia patients were rated as having significantly more executive failures than memory failures, whereas the brain-damaged patients showed the reverse pattern. Both groups of patients showed similar consistency of performance across sessions. CONCLUSIONS: Neuropsychological impairment in schizophrenia resembles that seen in patients with brain damage, not only in terms of overall severity, but also in terms of stability and the degree to which poor test performance translates into cognitive failures in daily life.     

Single domain amnestic MCI: A multiple cognitive domains fMRI investigation

Amnestic mild cognitive impairment (a-MCI) is associated with the highest annual incidence of conversion to Alzheimer's disease (AD) (10-15%). a-MCI patients may have only a memory deficit (single domain: sd-a-MCI) or additional dysfunctions affecting other cognitive domains (multiple domain: md-a-MCI). Using functional magnetic resonance imaging (fMRI), we investigated brain activation in 16 sd-a-MCI patients and 14 controls during four different tasks assessing language, memory, attention and empathy functions. We found greater activation in sd-a-MCI compared with controls in the left inferior temporal gyrus (language), the right superior temporal gyrus (memory) and the right dorsal precentral gyrus (attention). Moreover, patients’ activation correlated significantly with neuropsychological scores obtained at tests exploring the corresponding function. These findings indicate that fMRI is sensitive to detect early changes occurring in AD pathology and that individuals with sd-a-MCI show increased activation in multiple task-related brain regions. We suggest that these functional changes relate to the development of early compensatory mechanisms that reduce cognitive deficits associated with the progressive accumulation of brain damage.