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.

Standardised measurement of self-awareness deficits in FTD and AD.

BACKGROUND: Diminished ability to perceive one's own impairments, whether cognitive or social, is common in dementia, in particular frontotemporal dementia (FTD), where 'lack of insight' is listed as a core diagnostic feature. Yet, there is no currently accepted method for measuring insight in dementia. The most commonly used methods, which involve comparing patients' opinions of their level of impairment with the opinions of care givers or close family members, are subjective and require the participation of a knowledgeable informant. Here, the authors introduce a new method that allows objective quantification of an individual's awareness of their cognitive abilities and relies upon objective bedside testing. METHODS: The authors administered several tests of everyday, real-world functions to patients with FTD (n=10) and Alzheimer's disease (AD, n=10) and to control subjects (n=10). Prior to the tasks, participants were asked to predict their performance using a percentile-based rating system. They were also asked to estimate their performance after task completion. Differences between their self-rated and actual performances were calculated. RESULTS: Whereas the control group showed very little discrepancy between pretest predictions, post-task estimates and actual performance (mean difference of 3.9 percentile points for prediction/3.0 percentile points for post-task estimate), both patient groups overpredicted and overestimated their performance, with a significantly greater discrepancy for FTD (49.0/54.3 percentile points) than AD (27.2/28.3 percentile points). DISCUSSION: Failures of insight and self-awareness of cognitive dysfunction can be objectively measured in dementia without the assistance of an informant, which will facilitate further study of this key component of higher cognitive 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.

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.

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.

The measurement of everyday cognition (ECog): scale development and psychometric properties.

This article describes the development and validation of an instrument to assess cognitively mediated functional abilities in older adults, Everyday Cognition (ECog). The ECog is an informant-rated questionnaire comprised of multiple subscales. Confirmatory factor analysis (CFA) was used to examine its factor structure. Convergent validity was evaluated by comparing it to established measures of everyday function. External validity was evaluated by comparing ECog results across different clinical groups [cognitively normal, mild cognitive impairment (MCI), dementia]. CFA supported a seven-factor model including one global factor and six domain-specific factors (Everyday Memory, Language, Visuospatial Abilities, Planning, Organization, and Divided attention). The ECog correlated with established measures of functional status and global cognition, but only weakly with age and education. The clinical groups performed differently in each domain. In addition to the global factor, the Everyday Memory factor independently differentiated MCI from Normal, while the Everyday Language domain differentiated Dementia from MCI. Different subtypes of MCI also showed different patterns. Results suggest the ECog shows promise as a useful tool for the measurement of general and domain-specific everyday functions in the elderly.

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.

Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials.

BACKGROUND: Mild cognitive impairment (MCI) represents a transitional state between the cognitive changes of normal aging and very early dementia and is becoming increasingly recognized as a risk factor for Alzheimer disease (AD). The Memory Impairment Study (MIS) is a multicenter clinical trial in patients with MCI designed to evaluate whether vitamin E or donepezil is effective at delaying the time to a clinical diagnosis of AD. OBJECTIVE: To describe the baseline characteristics of patients with MCI recruited for the MIS and compare them with those of elderly controls and patients with AD in another clinical trial. DESIGN: Descriptive and comparative study of patients with MCI participating in a multicenter clinical trial. SETTING: Memory disorder centers in the United States and Canada. PATIENTS: A total of 769 patients with MCI, 107 cognitively normal elderly controls, 122 patients with very mild AD (Clinical Dementia Rating [CDR] 0.5), and 183 patients with mild AD (CDR 1.0) were evaluated. Patients in the MIS met operational criteria for amnestic MCI. Controls were recruited in parallel with the MCI group, underwent the same assessments, and had a CDR of 0. MAIN OUTCOME MEASURES: Clinical, neuropsychologic, functional, neuroimaging, and genetic measures. RESULTS: Mean +/- SD Alzheimer's Disease Assessment Scale-Cognitive Subscale scores were 5.6 +/- 3.3 for controls, 11.3 +/- 4.4 for patients with MCI, 18.0 +/- 6.2 for the AD CDR 0.5 group, and 25.2 +/- 8.8 for the AD CDR 1.0 group. Compared with controls, patients with MCI were most impaired on memory tasks, with less severe impairments in other cognitive domains. Patients with MCI were more likely than controls but less likely than patients with AD to carry the apolipoprotein E epsilon4 allele. Patients with MCI had hippocampal volumes that were intermediate between those of controls and patients with AD. CONCLUSIONS: Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings. These results demonstrate the successful implementation of operational criteria for this unique group of at-risk patients in a multicenter clinical trial.

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.

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.

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.

MCI is associated with deficits in everyday functioning.

The purpose of the present study was to examine the types of impairments in everyday function that accompany mild cognitive impairment (MCI). Data for this study was collected from 434 individuals consecutively evaluated at a university-based Alzheimer's Center. A total of 96 participants were diagnosed with MCI, 105 were cognitively normal, and 233 had dementia. Informant ratings of participants' abilities were obtained across different functional domains reflecting everyday abilities related to memory, language, visual spatial abilities, planning, organization, and divided attention. As expected, the demented group was significantly more impaired than the healthy control and MCI groups across all of the functional domains. The MCI group also showed significantly more functional impairment relative to healthy controls in all of the functional domains. Examination of the effect sizes as a measure of the magnitude of functional impairment in the MCI groups relative to controls showed that the greatest degree of impairment occurred within the Everyday Memory domain. The current findings suggest that individuals with MCI demonstrate deficits in a wide range of everyday functions but that the magnitude of these changes is greatest for those functional abilities that rely heavily on memory.

Cognitive predictors of functional decline in vascular dementia.

BACKGROUND: This study examined changes in cognitive-functional relationships in vascular dementia (VaD) over the course of one year. METHODS: Twenty-four patients with probable VaD were administered the Dementia Rating Scale (DRS). Caregivers completed an informant-based measure of instrumental (IADL) and basic activities of daily living (BADL). Follow-up assessment was conducted one-year post-baseline. RESULTS: Logistic regression revealed that changes in the DRS Initiation/Perseveration and DRS Memory subscales were significantly associated with declines in IADLs and BADLs, respectively. CONCLUSIONS: Among patients with VaD, longitudinal changes in IADLs and BADLs are most strongly associated with changes in executive functioning and memory abilities, respectively. Findings suggest that different cognitive functions subserve complex instrumental and rote, habituated basic functional activities, and neuropsychological screening measures are useful in the prediction of such functional changes.

Assessment and prediction of functional impairment in vascular dementia.

Vascular dementia is associated with cognitive, physical and functional impairments that often lead to disability among the elderly. Declines in activities of daily living significantly contribute to the disability reported among patients with vascular dementia and compromise quality of life for both patients and their families. Assessment of activities of daily living is an important component of the diagnosis, tracking and management of vascular dementia patients. Furthermore, an understanding of the determinants of activities of daily living dysfunction may provide an earlier identification of individuals at risk for functional disability and allow opportunities for improved patient care. In this review, methods for assessing and tracking activities of daily living are discussed and the literature on the correlates of functional impairment in vascular dementia is summarized. Also, the potential use of executive dysfunction as a marker for instrumental activities of daily living impairment is discussed and recommendations for clinical practice and future research are provided.

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.

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

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.

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.

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.