Verbal and design fluency in patients with frontal lobe lesions.

The ability to generate items belonging to categories in verbal fluency tasks has been attributed to frontal cortex. Nonverbal fluency (e.g., design fluency) has been assessed separately and found to rely on the right hemisphere or right frontal cortex. The current study assessed both verbal and nonverbal fluency in a single group of patients with focal, frontal lobe lesions and age- and education-matched control participants. In the verbal fluency task, participants generated items belonging to both letter cues (F, A, and S) and category cues (animals and boys' names). In the design fluency task, participants generated novel designs by connecting dot arrays with 4 straight lines. A switching condition was included in both verbal and design fluency tasks and required participants to switch back and forth between different sets (e.g., between naming fruits and furniture). As a group, patients with frontal lobe lesions were impaired, compared to control participants, on both verbal and design fluency tasks. Patients with left frontal lesions performed worse than patients with right frontal lesions on the verbal fluency task, but the 2 groups performed comparably on the design fluency task. Both patients and control participants were impacted similarly by the switching conditions. These results suggest that verbal fluency is more dependent on left frontal cortex, while nonverbal fluency tasks, such as design fluency, recruit both right and left frontal processes.     

Verbal fluency predicts mortality in Alzheimer disease.

OBJECTIVES: To assess the predictive value of neuropsychologic profiles, at diagnosis, for mortality in incident Alzheimer disease (AD). BACKGROUND: Rate of AD progression varies significantly across individuals for reasons that are not well understood. Several studies have linked rapid decline with disproportionately impaired executive functioning, presumably reflecting greater impairment of frontal networks. To the extent that differential neuropsychologic profiles reflect various neuropathologic presentations of AD, such profiles may inform survival estimates early in the disease. METHODS: Five neuropsychologic indices were used to characterize performance in 161 individuals at diagnosis of AD during a 15-year, longitudinal, primarily community-based study. RESULTS: Fifty-two percent of participants reached the mortality end point with a median survival of 5.52 years (95% confidence interval, 4.41-6.63). Cox proportional hazards analyses indicated that older age at diagnosis was associated with higher risk of mortality (risk ratios, 1.08; 95% confidence interval, 1.04-1.12) whereas Hispanic ethnicity predicted lower mortality [0.22 (0.09-0.55)]. Controlling for these 2 demographic variables, higher verbal fluency scores at diagnosis predicted lower mortality [0.69 (0.49-0.96)]. CONCLUSIONS: Disproportionate impairment of both category and letter fluency at the earliest stages of AD predicts mortality. The prognostic value of these tests may derive from their general psychometric properties, or may reflect the measures' sensitivity to an early or critical level of compromise to frontal networks.     

Verbal fluency performance in dementia of the Alzheimer's type: a meta-analysis

A meta-analysis of 153 studies with 15,990 participants was conducted to compare the magnitude of deficits upon tests of phonemic and semantic fluency for patients with dementia of the Alzheimer's type (DAT) relative to healthy controls. As has been found for patients with focal temporal cortical lesions (but not for patients with focal frontal cortical lesions), DAT patients were significantly more impaired on tests of semantic relative to phonemic fluency (r=0.73 and 0.57, respectively). Thus, since phonemic and semantic fluency are considered to impose comparable demands upon executive control processes such as effortful retrieval, but the latter is relatively more dependent upon the integrity of semantic memory, these results suggest that the semantic memory deficit in DAT reflects a degradation of the semantic store. Also supporting this conclusion, confrontation naming, a measure of semantic memory that imposes only minimal demands upon effortful retrieval, was significantly more impaired than phonemic fluency (r=0.60 versus 0.55, respectively). However, since semantic fluency was also significantly more impaired than confrontation naming (r=0.73 versus 0.61), deficits in semantic memory and effortful retrieval may be additive. Semantic, but not phonemic fluency, was significantly more impaired than measures of verbal intelligence and psychomotor speed. Thus, the semantic memory deficit in DAT qualifies as a differential deficit, but executive dysfunction as indexed by phonemic fluency does not constitute an additional isolated feature of the disorder. Dementia severity was not significantly related to the relative magnitude of deficits upon phonemic and semantic fluency.     

Verbal fluency patterns in amnestic mild cognitive impairment are characteristic of Alzheimer's type dementia.

Amnestic mild cognitive impairment (aMCI) represents a high-risk factor for Alzheimer's disease (AD) and is characterized by a selective decline in episodic memory. Although by definition aMCI is not associated with impaired verbal fluency performance, we examined relative differences between fluency tasks because AD is characterized by poorer semantic than phonemic fluency. Phonemic and semantic fluency trials were administered to 46 healthy controls, 33 patients with aMCI, and 33 patients with AD. Results revealed a progressive advantage (controls > aMCI > AD) in semantic, relative to phonemic fluency. Difference scores between tasks distinguished each group from the others with medium to large effect sizes (d) ranging from 0.49 to 1.07. Semantic fluency relies more on semantic associations between category exemplars than does phonemic fluency. This aMCI fluency pattern reflects degradation of semantic networks demonstrating that initial neuropathology may extend beyond known early changes in hippocampal regions.     

Planning impairments in frontal lobe dementia and frontal lobe lesion patients

Patients with frontal lobe brain damage are reportedly impaired on tasks that require plan development and execution. In this study, we examined the performance of 15 patients diagnosed with frontal lobe dementia and 14 patients with focal frontal lobe lesions on the Tower of London planning task. Patients with frontal lobe dementia committed a significantly higher number of rule violations, made more moves, and demonstrated longer solution time latencies compared to their matched controls. Patients with frontal lobe lesions demonstrated significantly delayed solution times and also made more moves compared to their matched controls. Frontal lobe lesion patient performance suggests an impairment in execution-related processes, while frontal lobe dementia patients appear to be impaired in both plan development and execution. Despite these findings, the identification of a specific cognitive impairment that induces these planning problems remains elusive.     

Comparisons of verbal fluency tasks in the detection of dementia of the Alzheimer type.

The performances of 89 patients with dementia of the Alzheimer type (DAT) and 53 demographically matched elderly normal control subjects were compared on four verbal fluency measures (category, letter, first names, and supermarket fluency). Receiver operating characteristic curves were plotted to determine each fluency tasks' sensitivity (ie, true-positive rate) and specificity (ie, true-negative rate). Category fluency demonstrated the greatest degree of discrimination between patients with DAT and normal control subjects (sensitivity, 100%; specificity, 92.5%); letter fluency was the least accurate (sensitivity, 89%; specificity, 85%). Separation of patients with DAT by gender revealed similar findings. In further analyses with a subgroup of 21 mildly impaired patients with DAT, category fluency lost none of its discriminative capabilities, whereas all other fluency measures showed marked reductions in discriminability. We conclude that this superiority of category fluency is due to its dependence on the structure of semantic knowledge, which deteriorates in the early stages of DAT.     

Verbal fluency and awareness of functional deficits in early-stage dementia

Assessment of activities of daily living is an important element in the diagnosis of dementia, with research suggesting a link between functional ability and cognition. We investigated the relationship between self- and informant ratings of instrumental activities of daily living (iADL) and verbal executive functioning in early-stage dementia. A total of 96 people with early-stage Alzheimer's disease or vascular or mixed dementia and their carers completed the Functional Activities Questionnaire; people with dementia also completed a test of letter fluency. Letter fluency was associated with self-ratings of iADL, while informant ratings of iADL were associated with the age and Mini-Mental State Examination score of the person with dementia. Self-ratings of perceived functioning suggested significantly less impairment than informant ratings. Those with impaired letter fluency rated themselves as having greater difficulties in iADLs than those who performed better. People with early-stage dementia vary in their subjective level of awareness of their iADL functioning, and difficulties with language production may contribute to better awareness of iADL impairments.     

Personality traits and frontal lobe dementia

The diagnosis of frontal lobe dementia (FLD) involves the assessment of affect. Three affective states predominate in FLD: apathy, elation and emotionalism. Nineteen FLD patients were investigated for a relationship between affective changes and premorbid personality traits. The negative results support the hypothesis that mood changes in FLD have a neurological basis and are important in early diagnosis.     

Verbal fluency, trail making, and Wisconsin Card Sorting Test performance following right frontal lobe tumor resection

Three commonly used clinical tests of frontal-executive function are verbal fluency, the Trail Making Test, and the Wisconsin Card Sorting Test, but few lesion studies of regional specificity within the frontal lobe (FL) exist for them. We examined 20 patients with right FL tumor resection, and mapped their damage to explore brain-behavior relations with greater precision. Across tests, the patients performed poorly and they also showed a deficit in switching but not clustering in verbal fluency. Within the right FL, however, we found none of the regional differences reported in studies of mixed-etiology FL patients, possibly due to the gradual neural reorganization that can occur with brain tumors. We discuss the importance of etiology in examining brain-behavior relations.     

Dementia of frontal lobe type.

A significant proportion of patients with presenile dementia due to primary cerebral atrophy do not have Alzheimer's disease. One form of non-Alzheimer dementia may be designated as dementia of frontal lobe type (DFT), on the basis of a characteristic neuropsychological picture suggestive of frontal lobe disorder, confirmed by findings on single photon emission tomography. The case histories of seven patients exemplify the disorder: a presentation of social misconduct and personality change, unconcern and disinhibition, in the presence of physical well-being and few neurological signs. Assessment revealed economic and concrete speech with verbal stereotypes, variable memory impairment, and marked abnormalities on tasks sensitive to frontal lobe function. Visuo-spatial disorder was invariably absent. Comparisons of DFT and Alzheimer patients revealed qualitative differences in clinical presentation, neurological signs, profile of psychological disability, electroencephalography, single photon emission tomography and demography. DFT, which may represent forms of Pick's disease, may be more common than is often recognised.     

Increased variability accompanies frontal lobe damage in dementia.

Performance variability on neuropsychological measures is not a unitary phenomenon, and different measures (consistency, dispersion, diversity) evaluate separate elements of variability. It has been suggested that increased variability may be a specific attribute of frontal lobe pathology. This hypothesis was tested in 2 matched groups of demented subjects, 8 with dementia of the Alzheimer type (DAT), 5 with frontal lobe dementia (FLD), compared with 10 elderly normal controls (ENC). A Stroop test and Reaction Time measures were administered weekly for 5 weeks to all subjects. Both measures contained three subtests varying in degree of complexity. The results from the Stroop task indicated that the FLD group showed significantly greater variability on measures of consistency (fluctuations over time) and diversity (between participant variability) regardless of the complexity of the subtest. For the Reaction Time subtests, measures of consistency and diversity showed significantly greater variability in FLD, but were affected in a different pattern. Greater variability in terms of consistency of performance was manifested only in the more attentionally demanding of the Reaction Time subtests (Choice Reaction Time, CRT). On the measure of diversity, variable performance was found to be greater on the Simple Reaction Time (SRT) subtest than on the more effortful CRT. Dispersion (within participant variability) was only assessed on the reaction time subtests. The results indicate no significant evidence for an increase in dispersion for the FLD patients. The hypothesis that variability will be increased in frontal lobe dementia is thus confirmed, and the independence of the three forms of variability measurement is demonstrated in dementia subjects.     

Tetrahydrobiopterin metabolism in the temporal lobe of patients dying with senile dementia of Alzheimer type.

There is a defect in tetrahydrobiopterin metabolism in brains from subjects with senile dementia of Alzheimer type compared to age-matched controls. This defect results in lowered total biopterin concentrations in brain. Brains from subjects with senile dementia of Alzheimer type retain their ability to synthesis neopterin and have normal dihydropteridine reductase activity, indicating a specific loss of ability to convert dihydroneopterin triphosphate to tetrahydrobiopterin.     

Agraphia in dementia of the Alzheimer type.

This study describes graphic errors made in writing a simple sentence in 368 healthy older adults and individuals in different stages of dementia of the Alzheimer type. Errors of agraphia were present in both healthy and demented people and, in general, increased with the severity of dementia. The errors of agraphia were not correlated with measures of aphasia or psychometric measures of language and motor performance. Writing skill may represent procedural memory, and agraphia errors indicate alterations in long-term memory in dementia of the Alzheimer type.     

Dissociation of two frontal lobe syndromes by a test of verbal fluency.

Numerous researchers have attempted to localise the behavioural manifestations of frontal pathology to the regions of the frontal lobe. Three prinicpal syndromes have been identified; the disinhibited syndrome associated with damage to the orbital area, the apathetic syndrome associated with damage to the frontal convexity, and the akinetic syndrome associated with damage to medial structures. This study attempted to determine if two of these syndromes could be dissociated from each other on the basis of a test of verbal fluency. This study used some commonly occurring clinical entities as the treatment groups. The orbitally lesioned individuals produced higher levels of disinhibited responding on the test than did non-orbitally lesioned subjects. However, all pathological groups produced lower overall levels of responding than did normals on the fluency component of the test. A number of suggestions are made as to why this may have been the case, and some guidelines for the clinical interpretation of response patterns on the fluency test are suggested.     

Neuropeptides in Alzheimer type dementia

Five neuropeptides (cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP), somatostatin (SRIF), neurotensin (NT) and substance P (SP)) were measured in 14 brain areas (4 cortical areas, hippocampus, amygdala, 3 striatal areas, 2 thalamic areas and 3 subcortical areas-- septum, substantia innominata and hypothalamus) in 12 brains with neuropathologically confirmed Alzheimer type change and in 13 control brains. Choline acetyltransferase (CAT) activity was assessed in 6 of these areas. Levels of SRIF, but not those of the other peptides, were reduced in several cortical areas in Alzheimer-type dementia (ATD). The distribution and magnitude of the reduction in SRIF were less than that of CAT activity and the temporal cortex was the only region in which there was a significant relationship between CAT and SRIF deficits. Peptide levels were unchanged in hippocampus, amygdala, thalamus, hypothalamus and striatum (except for an increase in SP in the putamen). SRIF levels were increased in substantia innominata in ATD. NT and SRIF were significantly, and VIP and SP non-significantly, reduced in the septum in ATD. Thus, apart from these alterations in the septum, SRIF was the only neuropeptide for which major changes were identified and these did not follow either the pattern of neuropathological change (e.g. in amygdala and hippocampus) or of CAT deficits (e.g. in substantia innominata).     

Cerebral blood flow and cerebral oxygen metabolism in patients with dementia of frontal lobe type

This study was designed to investigate the differences in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) between patients with dementia of frontal lobe type and patients with Alzheimer's disease. Positron emission tomography (PET) using 15O steady state inhalation technique was carried out in 5 patients with a clinical diagnosis of dementia of frontal lobe type and 7 patients with a clinical diagnosis of Alzheimer's disease. CBF and CMRO2 were significantly decreased in the frontal cortex except for precentral region in patients with dementia of frontal lobe type in comparison to those values in patients with Alzheimer's disease. However, in patients with dementia of frontal lobe type CBF and CMRO2 in the parietal cortex and the occipital cortex were relatively preserved when compared with patients with Alzheimer's disease. In comparison with values for CBF and CMRO2 in the posterior part of brain [frontal or temporal/(parietal + occipital)/2 ratio], both values in the frontal cortex were markedly decreased in all 5 patients with dementia of frontal lobe type, but there was no marked reduction in the frontal cortex in patients with Alzheimer's disease. In addition, in 2 patients with dementia of frontal lobe type whose duration of the disease was more than 7 years, CBF and CMRO2 in the temporal cortex were markedly reduced in comparison with values in the posterior part of brain. These results suggested that PET findings of marked reduction in CBF and CMRO2 in the frontal cortex are useful to distinguish dementia of frontal lobe type from Alzheimer's disease.