The N-monophenylcarbamate analogues of neostigmine methyl sulfate (6) and pyridostigmine bromide (8) together with their precursors (5),(7), and the N(1)-methylammonium analogues of (?)-phenserine (12),(?)-tolserine (14),(?)-cymserine (16) and (?)-phenethylcymserine (18) were synthesized to produce long-acting peripheral inhibitors of acetylcholinesterase or butyrylcholinesterase. Evaluation of their cholinesterase inhibition against human enzyme ex vivo demonstrated that, whereas compounds 5-8 possessed only marginal activity, 12, 14, 16 and 18 proved to be potent anticholinesterases. An extended duration of cholinesterase inhibition was determined in rodent, making them of potential interest as long-acting agents for myasthenia gravis.

Neuropsychological studies in myasthenia gravis (MG) were undertaken to prove the central nervous involvement. However, they still produce contradictory results. In the present study, a battery of cognitive measures was administered to examine global cognitive functioning, verbal learning, attention, executive function and motor performance. Analysis of partial scores in verbal learning and response fluency trials did not reveal fatigue effect in MG patients. It was shown that in tasks requiring motor, and particularly oculomotor, involvement, the muscle fatigue could account for the deficits observed. Thus, impaired performance on some cognitive measures in MG should be interpreted as an effect of muscle fatigability rather than central nervous system involvement.

In 2000 a Task Force of the Myasthenia Gravis Foundation of America recommended development of a quality of life (QOL) measure specific for myasthenia gravis (MG). Extant investigations have relied solely on assessment of physical aspects of daily living in conceptualizing QOL, despite research that emphasizes the importance of including psychological factors. In the present study we developed a QOL questionnaire specific to MG (MG-QOL) that assesses both physical and psychological aspects of function. The MG-QOL questionnaire was administered as a secondary measure of efficacy in a recently completed prospective trial of mycophenolate mofetil involving 80 MG patients. Comparisons indicated that the MG-QOL performed better than a nondisease-specific measure of QOL, the SF-36, in demonstrating disease change as assessed by the primary measure, the Quantitative MG score (QMG). The MG-QOL correlated highly with the SF-36, and demonstrated stronger associations with independent physical ability ratings. Results from this study support the use of this new measure of QOL, both clinically and in treatment trials of MG.

The organophosphorus nerve agent soman is an irreversible cholinesterase (ChE) inhibitor that can produce long-lasting seizures and brain damage in which the neurotransmitters acetylcholine and glutamate are involved. These same neurotransmitters play key-roles in the auditory function. It was then assumed that exploring the hearing function may provide markers of the central events triggered by soman intoxication. In the present study, distortion product otoacoustic emissions (DPOAEs), a non-invasive audiometric method, were used to monitor cochlear functionality in rats administered with a moderate dose of soman (45mug/kg). DPOAEs were investigated either 4h or 24h post-challenge. In parallel, the effects of soman on whole blood and brain ChE activity and on brain histology were also studied. The first main result is that DPOAE intensities were significantly decreased 4h post-soman and returned to baseline at 24h. The amplitude changes were well related to the severity of symptoms, with the greatest change being recorded in the rats that survived long-lasting convulsions. The second main result is that baseline DPOAEs recorded 8 days before soman appear to predict the severity of symptoms produced by the intoxication. Indeed, the lowest baseline DPOAEs corresponded to the occurrence of long-lasting convulsions and brain damage and to the greatest inhibition in central ChE. These results thus suggest that DPOAEs represent a promising non-invasive tool to assess and predict the central consequences of nerve agent poisoning. Further investigations will be carried out to assess the potential applications and the limits of this non-invasive method.

Here we report how the different types of regional muscle involvement, i.e. bulbar, ocular or generalized, in patients with myasthenia gravis (MG) influence the mental aspects of quality of life. Clinical examination according to Osserman was performed in 48 MG patients (45 women, three men; mean age 54, SD 12 years). Each patient was at the time for clinical evaluation asked to fill out the disease-specific Myasthenia Gravis Questionnaire (MGQ) and the Short-Form 36-item questionnaire for health survey (SF-36) as patient-oriented tools. We related the regional domains (generalized domain, bulbar domain and ocular domain) of the MGQ and the clinical findings, respectively, with mental quality of life as assessed by SF-36. Bulbar and generalized involvement results in impairment of mental aspects of quality of life, whereas ocular involvement does not.

We examined ratings of fatigue and cognitive performance in myasthenia gravis (MG) patients and healthy subjects. All participants were administered self-report measures of mental and physical fatigue before and after completing a demanding cognitive work battery. Change in fatigue indices was recorded and examined in relation to cognitive function. Results of the study revealed that baseline ratings of fatigue did not relate to cognitive performances for either group. By contrast, increased mental fatigue from the baseline to the post-test assessment correlated with cognitive measures for patients but not control subjects. MG patients reported that physical fatigue also increased following the work battery, but only ratings of mental fatigue correlated with cognitive performances. The results indicate that cognitive impairments may be associated with perceived fatigue in MG.

The cardinal symptom of myasthenia gravis (MG) is weakness of voluntary muscles, a feature that may restrict full participation in life activities. In turn, such limitations may negatively affect quality of life (QOL) and well-being among individuals with the disease. In the present study, we administered a measure of QOL to 27 patients with generalized MG. Results revealed that functional status was negatively impacted in the domains of physical functioning, energy, and general health. However, a clinically meaningful difference was evident only on perceived ability to accomplish physical tasks. The results suggest that although MG requires accommodations in physical activities, general QOL and well-being does not differ markedly from the general population.

Most individuals with myasthenia gravis (MG) complain of cognitive impairment, but empirical studies of cognition in MG have produced mixed results. In the present review, we critically examined the methodology and results of previous studies that investigated cognition in MG. Results from our review revealed that none of the studies met at least 50% of criteria under review. The most common shortcomings of previous studies included small sample size, no exclusion for visual difficulties in patients, inadequate assessment of mood, and poor control for prednisone use. Despite these methodological difficulties, mild impairments on measures of learning have been identified. These findings need to be replicated with adequate control of potential confounds before any conclusions can be made regarding cognition in this disease. Suggestions for design of future studies are provided.

The mood, self-evaluative, and vegetative symptoms of depression in myasthenia gravis were assessed. The frequency of depression was significantly elevated only when assessed by measuring vegetative symptoms. These findings suggest that mood in neuroimmune disorders should be assessed with scales that separate the different dimensions of depression.

We have examined fatigue in myasthenia gravis (MG) by administering a measure of cognitive and physical fatigue to patients and control subjects before and after administration of a lengthy cognitive battery. Subjects also completed a scale that assessed the impact of fatigue on physical, social, and cognitive function. Results of the study revealed that MG patients experience significantly more cognitive and physical fatigue than do control subjects, and the patients' perceptions of both cognitive and physical fatigue increased significantly following completion of demanding cognitive work. Control subjects reported no significant change in fatigue. Furthermore, MG patients reported that fatigue produced mild to moderate effects on cognitive and social function and moderate effects on physical function. Results from this study indicate that cognitive fatigue is an important symptom of MG and that fatigue produces pervasive impairments in important aspects of patients' lives. Additional studies are needed to understand the neurobehavioral determinants of cognitive fatigue in this population.

Recent findings suggest obesity is associated with reduced memory performance in older adults. The present study examined whether similar deficits also exist in younger adults and the degree to which the relationship between body mass index (BMI) and memory varies as a function of age. Prior to inclusion, participants were rigorously screened and excluded for medical conditions known to impact cognitive functioning, including neurological disorders, head injury, cardiovascular disease, and diabetes. A total of 486 healthy adults completed a verbal list-learning task. Participants were categorized into normal weight, overweight, and obese groups based on their BMI. Performance on learning, delayed recall, and recognition performance were compared across BMI groups. Results showed obese individuals had poorer memory performance when comparing persons across the adult lifespan (age 21-82 yr), but also when examining only younger and middle-aged adults (age 21-50 yr). Regression analyses found no evidence of an interaction between BMI and age on any memory variable, suggesting the relationship between BMI and memory does not vary with age. These findings provide further support for an independent relationship between obesity and reduced memory performance and suggest these effects are not limited to older adults. Further research is needed to identify etiological factors.

BACKGROUND The relationship between subcortical hyperintensity (SH) on magnetic resonance imaging (MRI), cortical perfusion on single photon emission computed tomography (SPECT), and cognitive function is not well understood. The authors examined these relationships in individuals with vascular dementia (VaD), paying particular attention to frontal lobe function to determine whether the presence of SH on MRI was associated with frontal hypoperfusion on SPECT, which in turn would be associated with impairments of executive-attention function. METHODS Patients with vascular dementia (n = 26) were assessed on neurocognitive tests and brain MRI and SPECT. SH volume was quantified from the axial T2-weighted fluid attenuated inversion recovery MRI. Total counts of activation across voxels for 12 cortical regions of interest were determined from SPECT. Perfusion ratios of both total cortical and frontal activation relative to cerebellum activation were derived, and regression analyses were performed to determine the relationships between cognitive, MRI, and SPECT indices. RESULTS SH volume on MRI was significantly associated with frontal lobe perfusion, but not with global cortical perfusion as measured by SPECT. Frontal lobe perfusion did not consistently correlate with performance on measures of executive-attention function, although both total and frontal perfusion ratios were significantly associated with other cognitive functions. CONCLUSIONS These results suggest that a functional "disconnection" between the frontal lobes and subcortical structures does not fully account for the magnitude of global cognitive impairment in VaD. Cortical perfusion as measured by SPECT appears to be associated with cognitive performance, but not specifically executive-attention dysfunction. Additional studies are needed to further examine the relationship between subcortical and cortical function in VaD.

OBJECTIVE To determine the relation between subcortical hyperintensities (SHs) visible on magnetic resonance imaging and executive function among patients with vascular dementia. BACKGROUND The relation between SHs and executive dysfunction is not well understood, because studies have varied widely in methodology and have produced conflicting results. METHOD We examined the relation between SHs (expressed as a percentage of total brain volume, not including ventricular volume) and six tests of executive function in a well-defined group of 24 individuals with vascular dementia. Executive tests were divided in two groups: Attention/Speed and Abstraction/Problem Solving. Bivariate correlations were computed between individual neuropsychological variables and SHs. RESULTS Results showed significant bivariate correlations between SHs and three of the four tests in the Attention/Speed domain. Subcortical hyperintensities shared virtually no association with performance on tests in the Abstraction/Problem-Solving domain. CONCLUSIONS The finding that SHs are significantly associated with psychomotor slowing and attentional dysfunction is consistent with what is known about the behavioral manifestations of subcortical disease. More detailed investigations of the regional distribution of SHs as well as measures of atrophy, hypoperfusion, and hypometabolism may be necessary to accurately characterize the complex relation between vascular disease and different aspects of executive dysfunction.

Impairment on screening measures such as the Mattis Dementia Rating Scale (MDRS) provides evidence of dementia in patients with cerebrovascular disease. However, the relationships between neuroimaging findings and performance on the MDRS in vascular dementia (VD) have not been determined. In the present study, we examined the relationships between subcortical hyperintensity (SH) volume and whole brain volume (WBV) on the subscales and total score of the MDRS. Results revealed that SH accounted for a significant amount of variance on the Initiation/Perseveration and Construction subscales, whereas WBV accounted for a significant amount of variance on the Memory subscale. The total score on the MDRS was found to be significantly related to WBV but not SH. These results suggest that subcortical damage and brain volume account for different aspects of cognitive decline in VD and that overall cognitive impairment may reflect cortical and subcortical involvement.

OBJECTIVES The purpose of this study was to examine the impact of neurocognitive and emotional distress and immune system dysfunction on quality of life in women with HIV. METHODS Thirty-six HIV-seropositive women were administered measures of mood status (Profile of Mood States), quality of life (Multidimensional Quality of Life Questionnaire for Persons with HIV) and cognitive function. CD4 cell counts were obtained as an indicator of immune system status. RESULTS Regression analyses revealed that independent of severity of emotional distress, neurocognitive deficits on measures of executive control and speed of information processing were associated with reduced quality of life. Emotional status also was associated with quality of life and together with neurocognitive performance accounted for most of the variance associated with quality of life. Reduced CD4 cell count was significantly associated with neurocognitive deficits, but not severity of emotional distress or quality of life. CONCLUSIONS Quality of life among women who are infected with HIV is strongly influenced by both neurocognitive and emotional status, as women with the greatest neurocognitive impairment and emotional distress report the poorest quality of life.

The defocused attention hypothesis (von Hecker and Meiser, 2005) assumes that negative mood broadens attention, whereas the analytical rumination hypothesis (Andrews and Thompson, 2009) suggests a narrowing of the attentional focus with depression. We tested these conflicting hypotheses by directly measuring the perceptual span in groups of dysphoric and control subjects, using eye tracking. In the moving window paradigm, information outside of a variable-width gaze-contingent window was masked during reading of sentences. In measures of sentence reading time and mean fixation duration, dysphoric subjects were more pronouncedly affected than controls by a reduced window size. This difference supports the defocused attention hypothesis and seems hard to reconcile with a narrowing of attentional focus.

A visual search task was used to investigate how visual attention and intraindividual variability changes with mild cognitive impairment (MCI). Specifically, we examined the contribution of shifting efficacy, distribution of attention, and controlled processing to declines in visual attention in two groups with MCI (single-domain amnestic and multi-domain amnestic), and measured changes in intraindividual variability. Our results demonstrate that visual search performance is attenuated in multi-domain amnestic MCI, but not single-domain amnestic MCI. In addition, we found that the multi-domain amnestic MCI group was more variable than the older controls and single-domain amnestic MCI participants. These between-group differences in search efficacy and intraindividual variability increased as a function of task complexity. We attribute these decrements in performance to changes in the control of attention and shifting efficacy, but not the distribution of attention.

The relationship between myasthenia gravis (MG) and cognitive dysfunction has been a matter of debate because of the possible association between peripheral and central nervous system (CNS) cholinergic dysfunction. The aim of this study was to evaluate cognitive function in a series of elderly MG patients in comparison to matched controls. In all, 100 consecutive MG patients aged over 60 years and 31 matched control subjects underwent an extensive neuropsychological test battery to explore multiple cognitive domains. There were no differences in cognitive performances between patients and controls. Severe MG was associated with impaired attention, constructional praxis, and frontal control. Logistic regression analysis showed that advanced age, diabetes, and thyroid dysfunction were independently associated with cognitive impairment. This study does not support the hypothesis of CNS cholinergic involvement in MG. The impairments of attention, memory, and control tasks in MG are related to general visual motor slowness and to the concomitant presence of other diseases.

The aim of the study was to determine whether infection with the hepatitis C virus (HCV) is associated with cognitive impairment beyond the effects of prevalent comorbidities and a history of substance use disorder (SUD). Adult veterans were recruited from the Portland Veterans Affairs Medical Center into three groups:(1) HCV+/SUD+(n = 39),(2) HCV+/SUD-(n = 24), and (3) HCV-/SUD-(n = 56). SUD+ participants were in remission for > or =90 days, while SUD- participants had no history of SUD. Groups did not significantly differ in terms of rates of psychiatric or medical comorbidities. Procedures included clinical interviews, medical record reviews, and neuropsychological testing. Significant group differences were found in the domains of Verbal Memory, Auditory Attention, Speeded Visual Information Processing, and Reasoning/Mental Flexibility (p <or =.05). Post hoc comparisons indicated that HCV+/SUD- patients performed significantly worse than HCV-/SUD- controls on tests measuring verbal learning, auditory attention, and reasoning/mental flexibility, but only HCV+/SUD+ patients did worse than HCV-/SUD- controls on tests of speeded visual information processing. Results indicate that chronic HCV is associated with cognitive impairment in the absence of a history of SUD. The most robust deficits appear to be in verbal learning and reasoning/mental flexibility.(JINS, 2009, 15, 69-82.).

OBJECTIVE Neuropsychological studies of bipolar disorder reveal deficits in a variety of domains, including affective processing, memory, and sustained attention. These findings are difficult to interpret due to the potential confounding effects of mood-stabilizing medications. The present study aims to compare the cognitive performance of medicated and unmedicated subjects with bipolar depression to healthy control subjects. METHOD Unmedicated subjects with bipolar depression (UBD, n = 32), subjects with bipolar depression on therapeutic doses of lithium or valproic acid (MBD, n = 33), and healthy control subjects (HC, n = 52) performed neuropsychological tasks measuring affective processing, visual memory, and sustained attention. Performance measures were covaried with age and mood ratings, where applicable. RESULTS With regard to affective processing, the MBD group exhibited greater response latency than the UBD and HC groups. For the same task, the MBD group made more omission errors during the happy condition than in the sad condition. On a task of sustained attention, the MBD group made more errors than the HC group. There were no significant group differences on measures of visual memory. CONCLUSIONS Deficits in affective processing were found in the medicated group, while unmedicated subjects appear to be unaffected. In particular, the MBD group made more errors during happy conditions, indicating a potential attentional bias in subjects with bipolar depression on mood-stabilizing medications. The present study also implicates impairment in sustained attention for medicated subjects with bipolar disorder, particularly those with the type II variety.

Objective Methamphetamine (MAP) is an indirect dopamine agonist that can temporarily increase cognitive performance. However, its long-term abuse may cause dopamine depletion and consequent cognitive and attentional impairment. The worsening of visual functions in Parkinson's disease and their improvement after levodopa administration implicates the role of dopamine in the physiology of vision. This provides the rationale for the investigation of visual functions in abstaining MAP abusers. Methods We investigated changes in visually evoked potentials (VEPs) to pattern-reversal and motion-onset stimuli. Such changes serve as indices of visual information processing in the primary and associative areas in a group of recently abstaining MAP abusers (5 females, 18 males, MAP abuse 5.3 +/- 2.8 years) and in 23 age- and gender-paired controls. Results We did not find differences between the groups in visual acuity. In the group of MAP abusers we observed an attenuation of the early responses around 80 ms and a prolongation of the P1 peak latency after the reversal of high spatial frequency checkerboards (10 and 20 arcmin checks). Furthermore, an attenuation of the latter positive response (170-250 ms) was observed among all the stimuli in parieto-frontal derivations for the MAP abusers. Conclusions This is the first report suggesting a slowing and attenuation of VEP responses during visual processing in abstaining methamphetamine abusers.

OBJECTIVE The aim of this study is to evaluate the correlation between brain perfusion and cognitive dysfunction in spinocerebellar ataxia type 6 (SCA6) patients. METHODS Thirteen genetically confirmed SCA6 patients and 21 age- and education-matched control subjects were subjected to single photon emission computed tomography (SPECT) and neuropsychological tests. Brain perfusion was examined with SPECT analysis, while general cognition, verbal and visual memory, attention, visuospatial ability, language, executive function, depression, and anxiety were examined with the neuropsychological tests. RESULTS SCA6 patients showed prefrontal hypoperfusion, and impairments of visual memory, verbal fluency, and executive function compared to control subjects. These neuropsychological impairments in SCA6 patients were significantly correlated with a decrease in prefrontal perfusion. This relation was not correlated to other factors, such as age, education and severity of cerebellar ataxia, which are possible relevant factors associated with cognitive performance. CONCLUSIONS SCA6 patients have mild cognitive impairment, and correlating prefrontal hypoperfusion. These results indicate cognitive impairment in SCA6 patients resulting from prefrontal hypoperfusion.

BACKGROUND Recent studies have focused on the nature of cognitive dysfunction in bipolar patients. The purpose of the current study was to investigate cognitive performance of individuals with bipolar disorder compared to healthy control subjects during a well-established euthymic period. METHODS The sample consisted of 27 bipolar euthymic patients and 21 control subjects. Verbal and visual memory performance, attention, executive functions and psychosocial functions were evaluated for each participant. RESULTS Bipolar patients showed significant attentional deficit and executive dysfunction and also poor performance on verbal and visual memory tasks compared to the controls. Illness duration and lifetime total episode number and previous episode with psychotic features was associated with worsened performance on attention, executive and memory tasks. Psychosocial functioning was not associated with cognitive deficit. CONCLUSIONS The present study showed persistent cognitive impairment on inhibitory control and selective attention as well as poor performance on verbal and visual memory tests in a group of bipolar euthymic patients. The impaired neuropsychological performance was associated with duration of illness, total number of episodes per lifetime, and previous episodes with psychotic features. Attentional dysfunction seemed to be a trait abnormality for the sample studied.

UNLABELLED BACKGROUND. Evidence has mounted that some patients with schizophrenia experience remission of symptoms and restoration of social and vocational functioning. The purpose of this study was to identify neurocognitive variables associated with recovery from schizophrenia. METHOD Twenty-eight patients diagnosed with DSM-IV schizophrenia or schizoaffective disorder and who met our operational definition of recovery from schizophrenia underwent a battery of neurocognitive tests. These subjects were matched with schizophrenia patients who did not meet recovery criteria ('non-recovered') and with normal controls. RESULTS On tests of executive functioning, verbal fluency and verbal working memory, recovered subjects performed significantly better than non-recovered subjects and were comparable to normal controls. Patient groups did not differ on a test that assessed early visual processing, but both groups performed significantly worse than normal controls. CONCLUSIONS Three measures of frontal lobe functioning appear to be neurocognitive domains associated with recovery from schizophrenia. These findings help narrow the search for targets for cognitive remediation that may have implications for improving community functioning.

The Intermediate Visual and Auditory (IVA) Continuous Performance Test (CPT) and Neuropsychological Impairment Scale (NIS) were completed with adults diagnosed with mild traumatic brain injury (mTBI), adults diagnosed with Attention Deficit Hyperactivity Disorder (ADHD), and controls. On the IVACPT, the mTBI and ADHD groups performed significantly lower on the full and secondary scales for attention and response accuracy. For individual scales, the mTBI and ADHD groups showed lower performance on measures of reaction time, inattention, impulsivity, and variability of RT. The mTBI and ADHD groups showed similar patterns of performance on the IVA. On the NIS, the mTBI and ADHD groups reported more neuropsychological symptoms than the control group and the mTBI group reported more neuropsychological symptoms than the ADHD group. The results are discussed in regard to changes in cognitive processing and sustained attention in individuals diagnosed with mTBI and ADHD.