The underlying mechanisms of verbal fluency deficit in frontotemporal dementia and semantic dementia

Verbal fluency tasks are commonly used to explore semantic memory and executive functions. The aim of this study was to gain a better understanding of the cognitive and neural mechanisms underlying verbal fluency impairment in the frontal variant of frontotemporal dementia (fv-FTD) and in semantic dementia (SD). Semantic and phonemic fluency tasks were performed by 36 fv-FTD and SD patients and 18 elderly controls. We also carried out a neuropsychological investigation of semantic memory, working memory and shifting and updating processes. We performed correlative and regression analyses of fluency scores and neuropsychological data. In addition, patients underwent a resting positron emission tomography examination, and statistical parametric mapping was used to establish correlations between resting-state FDG uptake in the whole brain and fluency scores for each patient group. Both patient groups displayed impaired performances on both fluency tasks compared with controls, but with different patterns. While fv-FTD patients scored higher than SD patients on semantic fluency, their performances on the phonemic task did not differ. Correlation and regression analyses clearly demonstrated that the fv-FTD patients’ performances on both fluency tasks depended on their executive abilities, while those of the SD patients were hampered by the impairment of their semantic memory store. Correlations with resting FDG uptake were consistent with the results of the cognitive study. In fv-FTD, both fluency performances were related to the metabolism of the frontal lobes, while we observed significant correlations between performances on both fluency tasks and the left temporal lobe metabolism in SD.     

Comparison of executive and visuospatial memory function in Huntington''s disease and dementia of Alzheimer type matched for degree of dementia.

Groups of patients with Hungington's disease and probable dementia of Alzheimer type (DAT) matched for level of dementia on the basis of mini mental state examination scores were compared in several tests of visual memory and tests sensitive to frontal lobe dysfunction. Whereas recall of patients with DAT tended to be worse on the Kendrick object learning test, the two groups were equivalent on tests of sensorimotor ability and delayed matching to sample performance. By contrast, the patients with Huntington's disease were significantly worse on tests of pattern and spatial recognition, simultaneous matching to sample, visuospatial paired associates, and on three tests sensitive to frontal lobe dysfunction--namely, the Tower of London test of planning, spatial working memory, and a visual discrimination learning and reversal paradigm. The impairments in these tests, however, did not always qualitatively resemble those seen in patients with frontal lobe damage and may be more characteristic of primary neostriatal deficit. In the visual discrimination paradigm the patients with Hungtington's disease were significantly worse than the patients with DAT at the simple reversal stage, where they displayed significant preservation to the previously rewarded alternative. The results are consistent with the hypothesis that patients with Huntington's disease exhibit deficits in tests sensitive to frontostriatal dysfunction and that this form of intellectual deterioration is qualitatively distinct from that seen in Alzheimer's disease.     

Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: a prospective cohort study

BACKGROUND: Mild cognitive impairment has been regarded as a precursor to dementia of Alzheimer type, but not all patients with mild cognitive impairment develop dementia. OBJECTIVE: To determine whether depression may increase the risk of developing dementia. SETTING: The outpatient clinics of a community general hospital. DESIGN: Prospective cohort study. METHODS: A cohort of 114 patients with amnestic mild cognitive impairment was followed up for a mean period of 3 years. At baseline, the patients underwent memory tests, the Spanish version of the Mini-Mental State Examination, a verbal fluency test, the Geriatric Depression Scale, and the Clinical Dementia Rating Scale for staging purposes. Psychiatric examination for depression was based on structured interview and Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition criteria. We also carried out either computed tomography or magnetic resonance imaging of the brain. MAIN OUTCOME MEASURES: We carried out periodic evaluations based on the Mini-Mental State Examination, verbal fluency test, Geriatric Depression Scale, Blessed Dementia Rating Scale, and Clinical Dementia Rating Scale. The end point was the development of probable Alzheimer disease according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association. RESULTS: Depression was observed in 41 patients (36%) at baseline. After a mean period of 3 years, 59 patients (51.7%) developed dementia of Alzheimer type, and 6 died. Of the depressed patients, 35 (85%) developed dementia in comparison with 24 (32%) of the nondepressed patients (relative risk, 2.6; 95% confidence interval, 1.8-3.6). The survival analysis also showed that depressed patients developed dementia earlier than the nondepressed. Most patients with depression at baseline exhibited a poor response to antidepressants. CONCLUSIONS: We conclude that patients with mild cognitive impairment and depression are at more than twice the risk of developing dementia of Alzheimer type as those without depression. Patients with a poor response to antidepressants are at an especially increased risk of developing dementia.     

Vitamin B12 deficiency in dementia and cognitive impairment: the effects of treatment on neuropsychological function

BACKGROUND: Vitamin B12 assay is part of the routine investigation of dementia, although few studies have investigated the effects of treatment on cognition. We examined the effects of B12 treatment on neuropsychological function and disease progression in patients presenting with dementia or cognitive impairment. METHODS: From 1432 patients who were assessed at the Bristol Memory Disorders Clinic, 125 patients with low serum B12 were identified. Sixty-six patients presenting with dementia, and 22 with cognitive impairment were seen for a second assessment after treatment. Changes in neuropsychological test scores were compared with those of patients with normal serum B12, matched by age and diagnosis. RESULTS: The majority of patients with low serum B12 had normal Hb and MCV values. We found no cases of reversible B12 deficiency dementia. The B12 treatment patients who presented with dementia showed no significant improvement, and no less deterioration, in their neuropsychological function than their matched group. However, a treatment effect was demonstrated among the patients presenting with cognitive impairment. These improved significantly compared to matched patients on the verbal fluency test (p<0.01). CONCLUSION: All patients with cognitive impairment should be investigated for B12 deficiency. Vitamin B12 treatment may improve frontal lobe and language function in patients with cognitive impairment, but rarely reverses dementia.     

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.     

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.     

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.     

Semantic memory is impaired in both dementia with Lewy bodies and dementia of Alzheimer's type: a comparative neuropsychological study and literature review

OBJECTIVE: To test the hypothesis that semantic impairment is present in both patients with dementia with Lewy bodies (DLB) and those with dementia of Alzheimer's type (DAT). METHODS: A comprehensive battery of neuropsychological tasks designed to assess semantic memory, visuoperceptual function, verbal fluency, and recognition memory was given to groups of patients with DLB (n=10), DAT (n=10) matched pairwise for age and mini mental state examination (MMSE), and age matched normal controls (n=15). RESULTS: Both DLB and DAT groups exhibited impaired performance across the range of tasks designed to assess semantic memory. Whereas patients with DAT showed equivalent comprehension of written words and picture stimuli, patients with DLB demonstrated more severe semantic deficits for pictures than words. As in previous studies, patients with DLB but not those with DAT were found to have impaired visuoperceptual functioning. Letter and category fluency were equally reduced for the patients with DLB whereas performance on letter fluency was significantly better in the DAT group. Recognition memory for faces and words was impaired in both groups. CONCLUSIONS: Semantic impairment is not limited to patients with DAT. Patients with DLB exhibit particular problems when required to access meaning from pictures that is most likely to arise from a combination of semantic and visuoperceptual impairments.     

Patterns of neuropsychological impairment in mild dementia: a comparison between Alzheimer's disease and multi-infarct dementia

The objective was to investigate the clinical and psychometric differences between patients with dementia of Alzheimer type (DAT) and patients with multi-infarct dementia (MID), matched for age, sex, education, and severity. Sixteen patients with DAT, 16 patients with MID, and 30 healthy individuals, were drawn from a longitudinal study on aging and dementia. Subjects with medical or previous mental disorders were excluded. DAT and controls with focal brain abnormalities on magnetic resonance imaging (MRI) were excluded. Diagnosis of dementia was carried out according to DSM-III-R criteria. Dementia severity was staged using the Clinical Dementia Rating (CDR) scale, and only patients with a score of 0.5-1 on CDR were studied. The main outcome measures were quantitative clinical scales of the assessment of global mental status, depression and anxiety, as well as a wide battery of neuropsychological tests for the evaluation of executive/conceptual functions and memory, as well as attention verbal ability, and visuospatial skill functions. The performance of demented patients compared to normal controls was affected on all measurements except for depression and anxiety. DAT patients showed compared to MID patients a greater extent of impairment on tasks assessing verbal comprehension and memory while MID patients were more significantly impaired on measures of frontal lobe functioning. Clinically matched DAT and MID patients show a differential pattern of neuropsychological impairment when studied in an early stage of dementia and with a mild degree of severity. Such patterns might be of value for the development of clinical diagnostic criteria.     

Neuropsychology of frontal type dementia]

The clinical conceptual change in frontal type dementia is reviewed in discussing its relationships to several related concepts such as Pick's disease, frontotemporal dementia (FTD), semantic dementia (SD) and frontotemporal lobar degeneration. We analyzed frontal type dementia selected from a consecutive series of our outpatients as to the details of neuropsychological symptoms, psychiatric symptoms, and abnormal behaviors. In our series of 143 patients with primary degenerative dementia, there were 16 cases of FTD and 6 cases of SD. Patients with two types of FTD and patients with SD were not distinguishable by neuropsychological examinations, behavioral abnormalities and psychiatric symptoms assessed with the Neuropsychiatric Inventory except for aphasia. The clinical picture of frontal type dementia involves frontal lobe symptoms such as disinhibition, apathy and stereotypy. Semantic memory loss for words, objects or faces suggestive of temporal lobe involvement developed only in patients with SD, and not in patients with FTD. Certain behavioral symptoms seen in frontal type dementia may respond to selective serotonin reuptake inhibitors. In care for patients with frontal type dementia, behavioral disturbances can be diminished and the quality of life can be improved by using their preserved procedural memory, pathological stereotypic behavior and stimulus-bound behavior such as utilization behavior and environmental dependency syndrome.     

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.     

Medullary arteries in aging and dementia

We examined sclerotic changes of the medullary arteries in 110 nonneuropsychiatric patients ranging in age from the second to the ninth decades, in 20 patients with subcortical arteriosclerotic encephalopathy (Binswanger's disease), and in 20 patients with dementia of the Alzheimer type. The principal sclerotic change was fibrohyaline thickening of the wall, which began to appear during the late fourth decade, increased in incidence gradually with age, and was most severe in patients with subcortical arteriosclerotic encephalopathy. Morphometry showed that the sclerotic changes of the medullary arteries were most prominent in the frontal lobe, followed by the parietal, occipital, and temporal lobes, in both the nonneuropsychiatric and demented groups. The sclerotic rate in the frontal lobe of patients with dementia of the Alzheimer type was slightly higher than that in the nonneuropsychiatric patients (p less than 0.05) but far less than that in the patients with subcortical arteriosclerotic encephalopathy (p less than 0.001). The sclerotic rate correlated well with the degree of ischemic white matter changes as well as with blood pressure.     

Nonspecificity of semantic impairment in dementia of Alzheimer's type

Two psychometric tests designed to evaluate "verbal fluency" and "naming" as a measure of semantic memory were presented to 18 patients with Alzheimer's-type dementia, 16 other patients with multi-infarct dementia, and 14 age-matched control subjects. The diagnosis of multi-infarct dementia and Alzheimer's-type dementia was based on the commonly accepted criteria of the Diagnostic and Statistical Manual of Mental Disorders, ed 3. Although the patients with Alzheimer and multi-infarct dementias, respectively, suffered from a comparable degree of dementia (as determined by the Mini-Mental State examination), semantic memory was not specifically impaired in Alzheimer's-type dementia as opposed to multi-infarct dementia. In contrast semantic memory was correlated with the degree of dementia in both disease entities.     

Bethanechol decreases reaction time in senile dementia of the Alzheimer type.

Bethanechol, a muscarinic cholinergic agonist, was injected subcutaneously in eight cases of senile dementia of the Alzheimer type. Simple reaction time was measured before, 15 min and 30 min following the injection. Before injection, the patients had significantly longer reaction time than non-demented controls. A significant shortening of the reaction time was observed 15 min but not 30 min after injection. A second group of eight patients with senile dementia of the Alzheimer type, matched for age and mental impairment were injected with saline. No significant shortening of the reaction time was observed. These results suggest that the reaction time can be shortened by a muscarinic agonist in dementia of the Alzheimer type.     

Influence of transcutaneous electrical nerve stimulation on memory in patients with dementia of the Alzheimer type.

This study examined the effect of transcutaneous electrical nerve stimulation (TENS) on memory in patients with dementia of the Alzheimer type. It was hypothesized that, in the early stage of the illness, electrical stimulation could activate the affected cortical regions by stimulating the neurotransmitter systems projecting to these areas. The results reveal that electrical stimulation improves the verbal long-term memory in these patients. Moreover, verbal fluency improves more in patients who received electrical stimulation than in patients who received control treatment. However, electrical stimulation does not influence the visual long-term memory of the patients, nor does it affect their verbal and nonverbal short-term memory. Underlying theoretical mechanisms are discussed.     

Influence of transcutaneous electrical nerve stimulation on memory in patients with dementia of the Alzheimer type

Abstract

This study examined the effect of transcutaneous electrical nerve stimulation (TENS) on memory in patients with dementia of the Alzheimer type. It was hypothesized that, in the early stage of the illness, electrical stimulation could activate the affected cortical regions by stimulating the neurotransmitter systems projecting to these areas. The results reveal that electrical stimulation improves the verbal long-term memory in these patients. Moreover, verbal fluency improves more in patients who received electrical stimulation than in patients who received control treatment. However, electrical stimulation does not influence the visual long-term memory of the patients, nor does it affect their verbal and nonverbal short-term memory. Underlying theoretical mechanisms are discussed.     

Wechsler intelligence scale profiles in Alzheimer type dementia and healthy ageing

Meta-analytic techniques were used to integrate the Wechsler Adult Intelligence (WAIS) scores of healthy elderly subjects and Alzheimer type dementia patients from 21 studies. Although age-scaled scores for demented subjects were lower than those of healthy elderly subjects for all subtests, the profiles for both groups were essentially parallel, with no subtest having significantly poorer scores than the others for the dementia patients. The pattern confirms other findings that verbal tests do not ‘hold’ to a greater degree than performance tests in dementia.     

A meta-analytic review of verbal fluency deficits in depression

A prominent view in the neuropsychological literature is that depression is particularly associated with deficits in executive control processes. A meta-analysis of 42 studies with 2306 participants was therefore conducted to investigate the sensitivity of tests of verbal fluency to the pressure of this disorder, as there is a great deal of evidence that theses measures are valid markers of executive dysfunction. When the methodology adopted by other meta-analytic reviews was employed, semantic fluency deficits were found to be substantially larger than the phonemic fluency deficits. However, when a more rigorous method of meta-analysis was adopted, this indicated that the measure are in fact broadly equivalent in their sensitivity to depression, as has been found for patients with focal frontal lobe lesions. However, in contrast to patients with focal frontal lobe injuries, neither deficit qualified as a differential deficit relative to psychomotor speed. Therefore, for patients with depression, deficits on tests of phonemic and semantic fluency may not reflect executive dysfunction, but a more generalized impairment. Evidence is presented that tests of phonemic and semantic fluency may aid in the differential diagnosis of patients with depression and those in the early stages of dementia of the Alzheimer's type.     

Verbal and Figural Fluency in Patients with Mass Lesions of the Left or Right Frontal Lobes

Impaired verbal and figural fluency has been shown to be associated with frontal lobe dysfunction. Jones-Gotman and Milner (1977) demonstrated a double dissociation between verbal and nonverbal fluency in a small sample of patients with frontal lesions of the left or right hemisphere. The present study has examined verbal and nonverbal fluency in 25 healthy participants and 95 patients with mass lesions of the left or right frontal lobes. In comparison with healthy participants, verbal fluency was reduced in patients with frontal lesions of the left hemisphere. Patients with right-sided lesions did not differ from either the control group or from the patients with left-sided frontal mass lesions. In the figural fluency task, the performance of the groups did not differ. The finding that patients with left frontal lesions produced fewer words than healthy paticipants suggests an association between left frontal lobe pathology and reduced verbal fluency. The results do not support the hypothesis of a double dissociation between verbal/figural fluency and the side of lesion within the frontal lobes.     

Cerebral metabolic and cognitive studies in dementia with frontal lobe behavioral features

Three subjects with dementia of the Alzheimer type (DAT) with frontal lobe features of behavioral disinhibition were studied using positron emission tomography with [18F]2-fluoro-2-deoxy-D-glucose (18 FDG) and standardized neuropsychological tests. The three subjects showed significant decrements (p less than .05) in relative glucose metabolism (regional/mean gray metabolism) in the orbitofrontal, prefrontal and anterior cingulate regions when compared to healthy controls. Severity-matched subjects with DAT without the associated frontal lobe features did not show the relative reductions in glucose metabolism in these regions when compared to controls. However, on neuropsychological testing of frontal lobe cognitive functions the three subjects did not show decrements that were more severe than those shown by severity-matched DAT patients without the behavioral features. These data demonstrate physiologic dysfunction in specific cortical regions in subjects with behavioral aberrations attributed to these regions and an apparent dissociation between behavioral and cognitive functions of the frontal lobe.