Dynamics of hemispheric dominance for language assessed by magnetoencephalographic imaging.

OBJECTIVE: The goal of the current study was to examine the dynamics of language lateralization using magnetoencephalographic (MEG) imaging, to determine the sensitivity and specificity of MEG imaging, and to determine whether MEG imaging can become a viable alternative to the intracarotid amobarbital procedure (IAP), the current gold standard for preoperative language lateralization in neurosurgical candidates. METHODS: MEG was recorded during an auditory verb generation task and imaging analysis of oscillatory activity was initially performed in 21 subjects with epilepsy, brain tumor, or arteriovenous malformation who had undergone IAP and MEG. Time windows and brain regions of interest that best discriminated between IAP-determined left or right dominance for language were identified. Parameters derived in the retrospective analysis were applied to a prospective cohort of 14 patients and healthy controls. RESULTS: Power decreases in the beta frequency band were consistently observed following auditory stimulation in inferior frontal, superior temporal, and parietal cortices; similar power decreases were also seen in inferior frontal cortex prior to and during overt verb generation. Language lateralization was clearly observed to be a dynamic process that is bilateral for several hundred milliseconds during periods of auditory perception and overt speech production. Correlation with the IAP was seen in 13 of 14 (93%) prospective patients, with the test demonstrating a sensitivity of 100% and specificity of 92%. INTERPRETATION: Our results demonstrate excellent correlation between MEG imaging findings and the IAP for language lateralization, and provide new insights into the spatiotemporal dynamics of cortical speech processing.

Everyday cognition in temporal lobe and frontal lobe epilepsy.

The purpose of this pilot study was to compare the performance of patients with temporal lobe epilepsy (TLE) and frontal lobe epilepsy (FLE) on cognitively-based daily living tasks. The hypothesis was that patients with TLE would demonstrate relatively more impairment on a test of everyday memory, while patients with FLE would demonstrate relatively more impairment on a test of everyday executive function. The five Daily Living subtests of the Neuropsychological Assessment Battery (NAB) were administered to twenty-five patients with TLE and nine patients with FLE. The two groups were matched on all demographic variables. The hypothesis was not confirmed: the TLE and FLE patient groups did not demonstrate a double dissociation in memory and executive daily functioning. Rather, both groups were significantly impaired in daily memory functioning, while their executive daily functioning test scores were within normal limits. Relative deficits were also noted in attention in the TLE group and in language in the FLE group, suggesting that despite having focal lesions, functional impairments may be seen in a broad range of daily activities in these patient groups. Generalizability of the findings is limited due to the small number of subjects and because the everyday cognition measures employed may not have been adequately sensitive. Future studies are needed with larger sample sizes to provide a better understanding of how cognitive impairment in epilepsy is associated with deficits in daily functioning.

Examination of volunteer bias in research involving patients diagnosed with psychogenic nonepileptic seizures.

There is some evidence to suggest that the same personality and emotional features observed in patients diagnosed with psychogenic nonepileptic seizures (PNES) may be related to nonparticipation in studies aimed at determining the most effective interventions for treating this patient population. This study aimed to document the frequency with which patients referred to an epilepsy monitoring unit (EMU) for video/EEG telemetry who are diagnosed with PNES or epileptic seizures (ES) participate in survey research. Of the 139 patients approached, 16 patients declined and 23 produced invalid or incomplete surveys. There was no significant difference in participation rates between patients diagnosed with PNES and those diagnosed with ES. These findings argue against a volunteer bias in research involving PNES and suggest that the results of other studies with these patients generalize to the population as a whole.

Longitudinal changes in memory and executive functioning are associated with longitudinal change in instrumental activities of daily living in older adults.

Impaired everyday function is a diagnostic criterion for dementia, and a determinant of healthcare utilization and caregiver burden. Although many previous studies have demonstrated a cross-sectional relationship between cognition (particularly executive functions and memory) and everyday function in older adults, very little is known about longitudinal relationships between these domains. This study examined the association between longitudinal change in episodic memory (MEM) and executive functioning (EXEC) and change in everyday function. Participants were a cognitively heterogeneous group of 100 elderly persons including those with normal cognition, as well as those with mild cognitive impairment and dementia. They were followed for an average of 5 years. Random effects modeling showed that change in both MEM and EXEC were independently associated with rate of change in informant-rated instrumental activities of daily living (IADLs), even after controlling for age, education, and gender. Findings indicate that declines in MEM and EXEC over time make unique and independent contributions to declines in older adults' ability to function in daily life.

Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: an open-label, phase I trial.

BACKGROUND: There is an urgent need for therapies that slow or reverse the progression of Parkinson's disease (PD). Neurotrophic factors can improve the function of degenerating neurons and protect against further neurodegeneration, and gene transfer might be a means to deliver effectively these factors to the brain. The aim of this study was to assess the safety, tolerability, and potential efficacy of gene delivery of the neurotrophic factor neurturin. METHODS: In this phase I, open-label clinical trial, 12 patients aged 35-75 years with a diagnosis of PD for at least 5 years in accordance with the UK Brain Bank Criteria received bilateral, stereotactic, intraputaminal injections of adeno-associated virus serotype 2-neurturin (CERE-120). The first six patients received doses of 1.3x10(11) vector genomes (vg)/patient, and the next six patients received 5.4x10(11) vg/patient. This trial is registered with ClinicalTrials.gov, number NCT00252850. FINDINGS: The procedure was well tolerated. Extensive safety monitoring in all patients revealed no clinically significant adverse events at 1 year. Several secondary measures of motor function showed improvement at 1 year; for example, a mean improvement in the off-medication motor subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) of 14 points (SD 8; p=0.000121 [36% mean increase; p=0.000123]) and a mean increase of 2.3 h (2; 25% group mean increase; p=0.0250) in on time without troublesome dyskinesia were seen. Improvements in several secondary measures were not significant, including the timed walking test in the off condition (p=0.053), the Purdue pegboard test of hand dexterity (p=0.318), the reduction in off time (p=0.105), and the activities of daily living subscore (part II) of the UPDRS (p=0.080). (18)F-levodopa-uptake PET did not change after treatment with either dose of CERE-120. INTERPRETATION: The initial data support the safety, tolerability, and potential efficacy of CERE-120 as a possible treatment for PD; however, these results must be viewed as preliminary until data from blinded, controlled clinical trials are available. FUNDING: Ceregene; Michael J Fox Foundation for Parkinson's Research.

Cognitive and neuroimaging predictors of instrumental activities of daily living.

Impaired ability to conduct daily activities is a diagnostic criterion for dementia and a determinant of healthcare services utilization and caregiver burden. What predicts decline in instrumental activities of daily living (IADLs) is not well understood. This study examined measures of episodic memory, executive function, and MRI brain volumes in relation to baseline IADLs and as predictors of rate of IADL change. Participants were 124 elderly persons with cognitive function between normal and moderate dementia both with and without significant small vessel cerebrovascular disease. Random effects modeling showed that baseline memory and executive function (EXEC) were associated with baseline IADL scores, but only EXEC was independently associated with rate of change in IADLs. Whereas hippocampal and cortical gray matter volumes were significantly associated with baseline IADL scores, only hippocampal volume was associated with IADL change. In a model including cognitive and neuroimaging predictors, only EXEC independently predicted rate of decline in IADL scores. These findings indicate that greater executive dysfunction at initial assessment is associated with more rapid decline in IADLs. Perhaps executive function is particularly important with respect to maintaining IADLs. Alternatively, executive dysfunction may be a sentinel event indicating widespread cortical involvement and poor prognosis.

Driving scenes test of the Neuropsychological Assessment Battery (NAB) and on-road driving performance in aging and very mild dementia.

The Driving Scenes test of the new Neuropsychological Assessment Battery (NAB; [Stern, R.A., & White, T. (2003a). Neuropsychological Assessment Battery. Lutz, FL: Psychological Assessment Resources, Inc.]) measures several aspects of visual attention thought to be important for driving ability. The current study examined the relationship between scores on the Driving Scenes test and on-road driving performance on a standardized driving test. Healthy participants performed significantly better on the Driving Scenes test than did very mildly demented participants. A correlation of 0.55 was found between the brief, office-based Driving Scenes test and the 108-point on-road driving score. Furthermore, the Driving Scenes test scores differed significantly across the driving instructor's three global ratings (safe, marginal, and unsafe), and results of a discriminant function analysis indicated that the Driving Scenes test correctly classified 66% of participants into these groups. Thus, the new NAB Driving Scenes test appears to have good ecological validity for real-world driving ability in normal and very mildly demented older adults.

Results of a randomized placebo-controlled study of memory training for mildly impaired Alzheimer's disease patients.

The efficacy of a memory-training program to improve word-list recall and recognition was evaluated in 34 patients with probable Alzheimer's disease (AD). The patients, who were all taking donepezil throughout the 6-week intervention, were randomly assigned to a cognitive intervention group or a control group. The Control group received didactic presentations but no formal memory training. Patients were assessed on neuropsychological tests before the 6-week training program, immediately after the training, and 8 weeks after completion of the training. Caregivers, who were blind to group assignment, completed activities of daily living (ADLs) and everyday memory questionnaires at all three time-points. No significant main effects of group (training vs. control) or time were observed on any outcome measures, nor were any significant interactions found. In terms of "process" measures during the 6-week training program, the patients demonstrated modest improvement on recall and recognition of test material presented during the training sessions. These results suggest that although modest gains in learning and memory may be evident in AD patients who are taught specific strategies, the benefits do not generalize to other measures of neuropsychological functioning after a brief intervention.

Neuropsychological predictors of everyday memory and everyday functioning in patients with mild Alzheimer's disease.

The contributions of executive function, naming, visuoperception, and delayed recall to everyday memory abilities and everyday living activities were examined in a sample (n = 24) of mildly impaired Alzheimer's disease (AD) patients. Everyday memory was rated independently by the patient and by a caregiver, and everyday functioning was rated by a caregiver. For patient-rated everyday memory, verbal recall accounted for 23% of the variance, while naming performance alone accounted for 56% of the variance in caregiver-rated everyday memory. Executive function was a unique and significant predictor of caregiver-rated functional daily living skills, accounting for 40% of the variance. Clinician's ratings of patient unawareness of deficit correlated with the discrepancy between caregiver and patient rating of memory. Caregiver reports of memory impairment appear to be influenced by naming abilities, indicating that language dysfunction may be misinterpreted as reflecting memory impairment. Helping caregivers distinguish between these two abilities may result in more accurate reporting of patients' impairments.

Discrimination of dementia with lewy bodies from Alzheimer disease and Parkinson disease using the clock drawing test.

OBJECTIVE: The authors' objective was to examine the ability of the Clock Drawing Test to discriminate Dementia with Lewy bodies from Alzheimer disease and Parkinson disease. BACKGROUND: Recent advances in medical treatments for dementia underscore the importance of differentiating among dementia subtypes. Clinically, Dementia with Lewy bodies can often be difficult to discriminate from Alzheimer disease and Parkinson disease because of similar and overlapping cognitive and motor features. While the Clock Drawing Test has been shown to discriminate dementia from normal aging fairly accurately, less is known about its ability to discriminate between various dementia groups. METHODS: Patients with Alzheimer disease (n = 22), patients with cognitively impaired Parkinson disease (n = 17), and patients with Dementia with Lewy bodies (n = 20), matched for age, education, and dementia severity, were compared on the Clock Drawing Test, scored for overall accuracy as well as the presence of specific error types. RESULTS: There were no significant group differences on a global quantitative measure of Clock Drawing Test performance. With regard to differences on the error types evaluated, the patients with Dementia with Lewy bodies were more likely to make conceptual errors than the patients with Alzheimer disease and Parkinson disease, and the patients with Parkinson disease and Dementia with Lewy bodies made more planning errors than the patients with Alzheimer disease. Classification accuracy was fair, with 69% overall classification for Alzheimer disease versus Dementia with Lewy bodies, and 68% overall classification for Parkinson disease versus Dementia with Lewy bodies. CONCLUSIONS: Although some differences may exist in the qualitative features of clock drawing performance between these patient groups, overall clock drawing performance is relatively similar, and as a single instrument, the Clock Drawing Test provides limited discrimination of Dementia with Lewy bodies from Alzheimer disease and Parkinson disease.

Executive dysfunction and apathy predict functional impairment in Alzheimer disease.

OBJECTIVE: The purpose of this study was to examine the extent to which executive cognitive dysfunction and frontally-mediated behavioral disturbances are associated with functional impairment in patients with mild-to-moderate Alzheimer disease (AD). METHODS: Patients with AD (N=45) completed the Mattis Dementia Rating Scale, and patients' caregivers completed the Frontal Systems Behavioral Inventory and a modified form of the Lawton and Brody Activities of Daily Living (ADLs) Questionnaire. RESULTS: Multiple-regression analyses revealed that executive cognitive dysfunction and apathy scores accounted for 44% of the variance in instrumental activities of daily living; executive cognitive dysfunction alone explained 17% of the variance in instrumental ADLs, and apathy scores explained an additional 27%. Executive dysfunction and frontal-behavioral impairment explained 28% of the variance in basic ADLs (BADLs), and, after accounting for executive dysfunction, apathy was the only symptom found to explain additional unique variance in BADLs. CONCLUSION: These findings suggest that specific cognitive and behavioral symptoms are associated with functional impairment in patients with AD.

Apathy and executive dysfunction in mild cognitive impairment and Alzheimer disease.

OBJECTIVE: The authors assessed and contrasted frontally mediated behavior changes in patients diagnosed with Mild Cognitive Impairment (MCI) and Alzheimer disease (AD). Apathy, executive dysfunction, and disinhibition are common in AD, but these behaviors have not been studied in MCI. METHODS: Participants were patients diagnosed with AD (n=25) or MCI (n=20). Current behavior and behavior before the onset of cognitive impairment was rated by knowledgeable informants on the Frontal Systems Behavior Scale (FrSBe). RESULTS: Apathy and executive dysfunction exhibited the greatest increase in both MCI and AD, and both increased significantly over baseline scores. No significant differences in behavior change were found between the two groups. Behavior change was moderately correlated with a measure of dementia severity, indicating that greater disease severity was associated with more abnormal behavior. CONCLUSION: Changes in frontally-mediated behaviors are common in very early and mild stages of cognitive impairment, even before functional decline in daily living is evident. These behaviors deserve more study in MCI because they may have implications for prognosis, treatment adherence, family distress, and patient quality of life.

Cognitive and behavioral features discriminate between Alzheimer's and Parkinson's disease.

OBJECTIVE: To compare the cognitive and behavioral profiles of Alzheimer's disease (AD) and cognitively impaired patients with Parkinson's disease (PD) and to determine the individual measures that best discriminate the two patient groups. BACKGROUND: Neuropsychologic studies of patients with AD and PD have generated debate over the distinction between "cortical" and "subcortical" dementias, with some studies showing significant differences and others showing little difference in the cognitive profiles of these groups. Studies evaluating behavioral differences between the patient groups have been somewhat more successful in adequately discriminating these syndromes. To address this issue, we examined cognitive and behavioral profiles of patients with AD and cognitively impaired patients with PD on two frequently used assessment instruments. METHOD: Patients were diagnosed according to published and accepted criteria for AD and PD. Eighteen patients with AD and 18 patients with PD, matched on age and education, were administered the Mattis Dementia Rating Scale and Frontal Systems Behavior Scale (formally Frontal Lobe Personality Scale). RESULTS: The two groups did not differ on overall Dementia Rating Scale score or total Frontal Systems Behavior Scale score. However, examination of subscale scores revealed that the patients with AD performed significantly worse than the patients with PD on the Memory subscale of the Dementia Rating Scale, and patients with PD were rated as being more apathetic than the patients with AD on the Frontal Systems Behavior Scale. When these two variables were entered into a discriminant function analysis, an overall classification accuracy of 86% was demonstrated, with 89% of the AD group and 83% of the PD group correctly classified. CONCLUSIONS: These findings suggest that even though global cognitive dysfunction and behavioral disturbance may appear similar in patients with AD and cognitively impaired patients with PD, specific measures of these functions that are sensitive to the underlying neuropathology of each disease do differ significantly.

The relationship of MRI subcortical hyperintensities to treatment response in a trial of sertraline in geriatric depressed outpatients.

The authors examined differences in antidepressant treatment response in geriatric outpatients with high vs. low levels of magnetic resonance imaging (MRI)-defined subcortical hyperintensities (SH). Participants included 59 outpatients with mild-to-moderate depression (mean age: 69+/-5.63 years; mean Hamilton Rating Scale for Depression score: 21+/-2.88) who participated in a placebo-controlled trial of sertraline and underwent a standardized brain MRI. Results revealed that the high-SH group was significantly older than the low-SH group but, contrary to the hypothesis, antidepressant treatment response did not differ between the high- and low-SH groups. The association between SH and antidepressant treatment response in depressed geriatric outpatients remains unclear and deserves further investigation.

Tests of executive function predict instrumental activities of daily living in community-dwelling older individuals.

The purpose of this study was to examine the utility of specific tests of executive functioning for predicting instrumental activities of daily living (IADLs) in community-dwelling older individuals (n = 30). In addition to tests of frontal and executive functioning, performance-based and caregiver-rated evaluations of IADLs were obtained. Results indicated that different tests of executive functioning were associated with outcomes on performance-based versus caregiver-rated assessments of IADLs. Specifically, the Trail Making Test (Part B) made a significant and unique contribution to the prediction of performance-based IADLs. In contrast, verbal fluency performance and Trail Making Test performance made significant independent contributions to the prediction of IADLs as reported by a caregiver. These findings suggest that different aspects of frontal and executive functions may be related to IADLs, depending on the type of assessment instrument used. Key words: activities of daily living, executive function, older adults