Impaired Frontal Lobe Function Research Articles

COGNITIVE FUNCTION AND INDEPENDENCE IN THE OLDEST-OLD: REVIEW STUDY BASED ON AGING IN PLACE

Some older adults desire to continue living in the community in which they reside. The concept of Aging in Place (AIP) is appropriate for this idea. For AIP to be successful, the oldest-old need to demonstrate their abilities and live safely, independently, and comfortably in their homes and communities. Conversely, AIP in an inappropriate manner, without a safe environment, and without support provided, comprising dangerous situations caused by declining cognitive and physical function, lead to reduced quality of life for older people. Therefore, this study aimed to examine cognitive function in the oldest-old to understand differences between normal aging and cognitive decline due to dementia. Cognitive decline due to normal aging in the oldest-old is caused by impaired frontal lobe function, while decline due to Alzheimer’s disease is caused by impaired temporal-parietal lobe function, suggesting that this impairment may be useful for achieving independence for AIP.

Prof K C Dube Poster Award

INTRODUCTION:Clinical, neurophysiological and functional neuroimaging studies in schizophrenia suggest impaired frontal lobe function, especially of the dorsolateral prefrontal cortex (DLPFC). Prefrontal dysfunction has been found to be associated with negative symptoms. Despite these findings, structural neuroimaging studies have failed to show consistent abnormalities in the frontal lobe. This may be because existing techniques are not sensitive enough to detect structural abnormalities or that dysfunction in the frontal lobe is caused by lesions elsewhere.AIM:We aimed to measure N-acetylaspartate (NAA), a neuronal marker, to evaluate the neuronal integrity of the dorsolateral prefrontal region in schizophrenic patients with persistent negative symptoms and in healthy comparison subjects, using proton magnetic resonance spectroscopy (1H-MRS).METHODOLOGY:Thirty six patients who fulfilled ICD-10 criteria for schizophrenia and with SANS score of more than 20 were compared to 15 healthy controls matched for age and gender. Proton Magnetic Resonance spectra were collected from the left dorsolateral prefrontal region with a voxel size of a 1.5cm3. In vivo 1H-MRS analyses were processed using Tarquin 4.3.10 software. Total NAA corresponding to the sum of NAA and N-Acetyl-Aspartyl-Glutamate (NAAG), was determined. NAA levels were calculated relative to the unsuppressed water signal from the same voxel.RESULTS:There were no significant differences between the two groups for NAA levels. There was no significant correlation between severity of symptoms and NAA concentration in the schizophrenic patients.CONCLUSION:The lack of significant mean difference in NAA between the two groups suggests that there is no marked neuronal loss in the dorsolateral prefrontal region in schizophrenia.

Cognitive Function in Genetic Generalized Epilepsies: Insights From Neuropsychology and Neuroimaging.

Genetic generalized epilepsies (GGE), previously called idiopathic generalized epilepsies, constitute about 20% of all epilepsies, and include childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone (CAE, JAE, JME, and GGE-GTCS, respectively). GGE are characterized by high heritability, likely underlain by polygenetic mechanisms, which may relate to atypical neurodevelopmental trajectories. Age of onset ranges from pre-school years, for CAE, to early adulthood for GGE-GTCS. Traditionally, GGE have been considered benign, a belief contrary to evidence from neuropsychology studies conducted over the last two decades. In JME, deficits in executive and social functioning are common findings and relate to impaired frontal lobe function. Studies using neuropsychological measures and cognitive imaging paradigms provide evidence for hyperconnectivity between prefrontal and motor cortices, aberrant fronto-thalamo-cortical connectivity, and reduced fronto-cortical and subcortical gray matter volumes, which are associated with altered cognitive performance. Recent research has also identified associations between abnormal hippocampal morphometry and fronto-temporal activation during episodic memory. Longitudinal studies on individuals with newly diagnosed JME have observed cortical dysmaturation, which is paralleled by delayed cognitive development compared to the patients' peers. Comorbidities and cognitive deficits observed in other GGE subtypes, such as visuo-spatial and language deficits in both CAE and JAE, have also been correlated with atypical neurodevelopment. Although it remains unclear whether cognitive impairment profiles differ amongst GGE subtypes, effects may become more pronounced with disease duration, particularly in absence epilepsies. Finally, there is substantial evidence that patients with JME and their unaffected siblings share patterns of cognitive deficits, which is indicative of an underlying genetic etiology (endophenotype), independent of seizures and anti-epileptic medication.

Moral judgment in patients with idiopathic generalized epilepsy

PurposeThe aim of the current study was to investigate morality while also investigating frontal lobe function with the goal of studying the relationship between frontal lobe and morality in patients with idiopathic generalized epilepsy. MethodA total of 23 right-handed patients with IGE and 25 right-handed healthy participants agreed to participate. Participants made judgments on a series of 50 hypothetical scenarios, which were adapted from a previously published set. The Stroop Test, verbal fluency, Digit Span tests and Wisconsin Card-Sorting Test were used to assess the frontal lobe function. ResultsIGE patients with impaired frontal lobe function choosed more utilitarian options than healthy controls in impersonal dilemmas but not in personal dilemmas. The performance of impersonal judgments were correlated positively with total errors positively and correlated negatively with categories completed. ConclusionsIGE patients with impaired frontal lobe function possessed unusual impersonal moral decision-making and those decisions may be caused more by cognitive impairment than by social-emotional impairment. Correlation analysis indicated that the unusual moral decisions correlated with frontal lobe dysfunction in patients with IGE.

The relationship between executive functions and fluid intelligence in schizophrenia.

An enduring question is unity vs. separability of executive deficits resulting from impaired frontal lobe function. In previous studies, we have asked how executive deficits link to a conventional measure of fluid intelligence, obtained either by standard tests of novel problem-solving, or by averaging performance in a battery of novel tasks. For some classical executive tasks, such as the Wisconsin Card Sorting Test (WCST), Verbal Fluency, and Trail Making Test B (TMTB), frontal deficits are entirely explained by fluid intelligence. However, on a second set of executive tasks, including tests of multitasking and decision making, deficits exceed those predicted by fluid intelligence loss. In this paper we discuss how these results shed light on the diverse clinical phenomenology observed in frontal dysfunction, and present new data on a group of 15 schizophrenic patients and 14 controls. Subjects were assessed with a range of executive tests and with a general cognitive battery used to derive a measure of fluid intelligence. Group performance was compared and fluid intelligence was introduced as a covariate. In line with our previous results, significant patient-control differences in classical executive tests were removed when fluid intelligence was introduced as a covariate. However, for tests of multitasking and decision making, deficits remained. We relate our findings to those of previous factor analytic studies describing a single principal component, which accounts for much of the variance of schizophrenic patients' cognitive performance. We propose that this general factor reflects low fluid intelligence capacity, which accounts for much but not all cognitive impairment in this patient group. Partialling out the general effects of fluid intelligence, we propose, may clarify the role of additional, more specific cognitive impairments in conditions such as schizophrenia.

Psychosis in Alzheimer’s Disease is Associated with Frontal Metabolic Impairment and Accelerated Decline in Working Memory: Findings from the Alzheimer's Disease Neuroimaging Initiative

An ascendant body of evidence suggests that Alzheimer disease with psychosis (AD+P) is a distinct variant of illness with its own genetic diathesis and a unique clinical course. Impaired frontal lobe function has been previously implicated in AD+P. The current exploratory study, presented in two parts, evaluates both the regional brain metabolic and psychometric correlates of psychosis in a longitudinal sample of subjects with AD, made available by the Alzheimer's Disease Neuroimaging Initiative (ADNI). In Part 1 of the study, 21 ADNI participants with AD who developed psychotic symptoms during the study but were not psychotic at baseline were matched with 21 participants with AD who never became psychotic during the study period, and mean brain [F(18)]fluorodeoxyglucose positron emission tomography (FDG-PET) Cerebral metabolic rate for glucose (CMRgl) by regions of interest (ROIs) were compared Additionally, 39 participants with active psychosis at the time of image acquisition were matched with 39 participants who were never psychotic during the study period, and mean brain FDG-PET CMRgl by sROI were compared. In Part 2 of the study, 354 ADNI participants with AD who were followed for 24 months with serial psychometric testing were identified, and cognitive performance and decline were evaluated for correlation with psychotic symptoms. Part 1: There were no regional brain metabolic differences between those with AD destined to become psychotic and those who did not become psychotic. There was a significant reduction in mean orbitofrontal brain metabolism in those with active psychosis. Part 2: Over the course of study follow-up, psychosis was associated with accelerated decline in functional performance as measured by the Functional Assessment Questionnaire, the Mini-Mental State Examination, and Forward Digit Span. In a sample drawn from the ADNI dataset, our exploratory FDG-PET findings and longitudinal cognitive outcomes support the hypofrontality model of AD+P. Focal frontal vulnerability may mediate the accelerated decline seen in AD+P.

Cognitive Consequences of Multiple Lacunes and Leukoaraiosis as Vascular Cognitive Impairment in Community-Dwelling Elderly Individuals

The aim of our study was to investigate the effects of silent brain lesions on cognitive function of community-dwelling elderly individuals. Brain magnetic resonance imaging and other medical examinations were performed on 350 nondemented elderly individuals (121 male and 229 female, average age 72.4 years) who resided in the rural community of Sefuri Village, Saga, Japan. The mini mental state examination and modified Stroop test (MST) were used to identify cognitive impairment. White matter lesions (WMLs) and cerebral atrophy on magnetic resonance imaging were measured quantitatively. Multivariate analyses were done using a logistic regression model with a software package. Cognitive impairment defined by mini mental state examination score less than 24 was present in 55 individuals (15.7%). They had a lower educational level, significantly larger quantity of WMLs, and more remarkable cerebral atrophy. Frontal lobe dysfunction was detected in 52 individuals (14.9%) through prolonged MST score (>36 seconds). Impaired frontal lobe function was related to number of silent lacunar infarcts, larger WMLs, and more prominent cerebral atrophy. MST score in individuals with two or more infarcts was significantly more prolonged compared with MST score in those without infarction. These results suggest that WMLs may cause rather diffuse cognitive decline, whereas multiple lacunar infarcts are specifically involved in frontal lobe dysfunction. Silent ischemic lesions in apparently healthy elderly individuals seem to form a distinctive group of people with vascular cognitive impairment without dementia. This group should be the primary target of prevention of vascular dementia.

Superior Frontal Cortex Cholinergic Axon Density in Mild Cognitive Impairment and Early Alzheimer Disease

Loss of cortical choline acetyltransferase (ChAT) activity contributes to end-stage Alzheimer disease (AD) dementia. In general, ChAT activity levels are stable in the neocortex in mild to moderate AD (mAD) and there is a selective up-regulation in the superior frontal cortex (SFC) in mild cognitive impairment (MCI), indicating a transient, region-specific cholinergic neuroplastic response. To assess whether a proliferation of cholinergic axons underlies increased ChAT activity levels in the SFC in subjects with MCI. Stereologic principles were applied to assess the density of ChAT-immunoreactive fibers and axon varicosities in SFC tissue obtained postmortem from subjects with no cognitive impairment, MCI, and mAD. Thirty-six subjects enrolled in the Religious Orders Study, with records of annual clinical evaluation for frontal lobe specific and global cognitive functions. Compared with the group with no cognitive impairment, SFC ChAT-immunoreactive fiber and axon varicosity densities were not altered in the MCI group but were significantly reduced in the group with mAD and correlated with impaired frontal lobe and global cognitive function. The lack of an increase in cholinergic axonal innervation of the SFC in MCI suggests that structural reorganization of cholinergic profiles is not the mechanism underlying the transient cholinergic plasticity reported in this region. Furthermore, the stability of cholinergic enzyme activity in mAD is likely the result of a biochemical up-regulation of ChAT protein or enzyme activity levels in the SFC, compensating for decreased regional cholinergic fibers and axon varicosities.

Longitudinal volumetric MRI change and rate of cognitive decline

To examine how baseline and change of volumetric MRI relate to cognitive decline in older individuals. Memory is associated with hippocampal integrity, whereas executive function has been linked to impaired frontal lobe function. Previous studies have shown that hippocampal and cortical atrophy are more strongly related to cognition than are measures of subcortical cerebrovascular disease (CVD). The authors hypothesized that memory (MEM) decline would be related to change in hippocampal volume (HC), whereas decline in executive function (EXEC) would be related to change of cortical gray matter volume (CGM) and measures of subcortical CVD. Subjects from a multicenter study (n = 103) included cognitively normal, mildly impaired, and demented cases with and without subcortical lacunes. All had longitudinal cognitive evaluation (mean = 4.8 years) and two or more MRI scans at least one year apart (mean = 3.4 years). MRI measures included HC, CGM, total lacune volume (LAC), and white matter hyperintensity volume (WMH). Random effects modeling of longitudinal data assessed effects of MRI baseline and MRI change on baseline and change of psychometrically matched measures of MEM and EXEC. Change in MEM was related to HC baseline and HC change. Change in EXEC was related to baseline CGM and to change in CGM, HC, and LAC. Results were unchanged when demented cases were excluded. WMH was not associated with change in MEM or EXEC independent of HC, CGM, and LAC. Hippocampal volume was the primary determinant of memory decline, whereas executive function (EXEC) decline was related to multiple brain components. Results support a hypothesis that MEM decline is strongly influenced by Alzheimer disease (AD), whereas EXEC decline may be complexly determined by cerebrovascular disease and AD.

Frontal lobe dysfunction caused by multiple lacunar infarction in community-dwelling elderly subjects

We examined the factors that influence frontal lobe function among 119 community-dwelling elderly subjects, based on magnetic resonance imaging (MRI) and clinical findings. We interviewed the subjects, and conducted a neurological examination, electrocardiogram, blood test, brain MRI examination, and cognitive function tests. The modified Stroop test and a personal computer version of the Wisconsin Card Sorting Test (WCST) were used to evaluate frontal lobe function. The subjects with impaired frontal lobe function defined by the modified Stroop test were significantly older, had more lacunar infarcts, and had lower HDL cholesterol values based on a logistic regression model. Among the aged who appear apparently normal, multiple lacunar infarcts are the cause of latent frontal lobe dysfunction.

Frontal lobe N-acetylaspartate correlates with psychopathology in schizophrenia: a proton magnetic resonance spectroscopy study.

Clinical, neuropsychological and functional neuroimaging studies in schizophrenia suggest impaired frontal lobe function, especially of the dorsolateral prefrontal region (DLPFR). This dysfunction has in particular been associated with negative or "deficit" symptoms. Despite these findings, morphological studies have failed to show consistent structural abnormalities in the frontal lobe. This may be because existing techniques are not sensitive enough to detect structural abnormalities or that dysfunction in the frontal lobe is caused by lesions elsewhere. We used volume-localised proton magnetic resonance spectroscopy (1H-MRS) to measure N-acetylaspartate (NAA), a neuronal marker, to evaluate the neuronal integrity of the dorsolateral prefrontal region in schizophrenic patients with persistent negative symptoms and in healthy comparison subjects. Twenty-five patients who fulfilled DSM-IV criteria for schizophrenia and met the criteria for the Deficit syndrome were compared to 26 healthy controls matched for age and gender. Bilateral proton MR spectra were collected from a 2-cm(3) volume in the dorsolateral prefrontal region and the absolute concentrations of N-acetylaspartate, choline (Cho) and creatine+phosphocreatine (Cr+PCr) were measured. There was a significant negative correlation between severity of symptoms and NAA concentration in the schizophrenic patients. This was more marked for positive symptoms and for general psychopathology than for negative symptoms. There was also a significant correlation between NAA concentration and social functioning within the schizophrenic group. There were no significant differences between the two groups for the three metabolites. The negative association between severity of symptoms and NAA in schizophrenic patients and an association of NAA with social functioning suggest that NAA may be an indicator of disease severity. The lack of significant mean difference in NAA between the two groups suggests that there is no marked neuronal loss in the dorsolateral prefrontal region in schizophrenia.

Selective attention is impaired in amyotrophic lateral sclerosis—a study of event-related EEG potentials

In humans, selective attention is assumed to be under control of the frontal lobe. A significant proportion of patients with amyotrophic lateral sclerosis (ALS) shows impairments in various tasks touching frontal lobe function. We, therefore, undertook a study of event-related EEG potentials (ERPs) in eight non-demented ALS patients in order to investigate a possible deficit of auditory selective attention: tones were presented in random sequence to the left or right ear, one of which was to be attended. The negative shift of the ERPs evoked by attended tones in relation to unattended tones (`processing negativity': PN) was smaller in ALS patients than in age-matched healthy control persons. This was true for Fz and Cz and for both a slow and a fast presentation rate of the tones. In the patients, reduced PN amplitude correlated with functional motor impairment. The utility of ERP testing to assess impaired frontal lobe function is shown for the first time in ALS patients. The results of our study fit to recent positron emission tomography (PET) and fMRI data.

420 Visual and auditory event related potentials in amyotrophic lateral sclerosis

In humans, selective attention is assumed to be under control of the frontal lobe. A significant proportion of patients with amyotrophic lateral sclerosis (ALS) shows impairments in various tasks touching frontal lobe function. We, therefore, undertook a study of event-related EEG potentials (ERPs) in eight non-demented ALS patients in order to investigate a possible deficit of auditory selective attention: tones were presented in random sequence to the left or right ear, one of which was to be attended. The negative shift of the ERPs evoked by attended tones in relation to unattended tones (`processing negativity': PN) was smaller in ALS patients than in age-matched healthy control persons. This was true for Fz and Cz and for both a slow and a fast presentation rate of the tones. In the patients, reduced PN amplitude correlated with functional motor impairment. The utility of ERP testing to assess impaired frontal lobe function is shown for the first time in ALS patients. The results of our study fit to recent positron emission tomography (PET) and fMRI data.

Familial and developmental abnormalities of front lobe function and neurochemistry in schizophrenia.

structural abnormalities of the cerebral cortex in schizophrenia have been revealed by magnetic resonance imaging, although it is not clear whether these abnormalities are diffuse or local. We predicted that changes in cortical structure would result in abnormalities in biochemical markers for the glutamate system in post-mortem brain, and that the pattern of neurochemical abnormalities would be a clue to the distribution and extent of pathology. A number of studies have now reported increases in biochemical and other markers of glutamatergic cell bodies and terminals in the frontal cortex in schizophrenia. These findings are consistent with the presence of an abnormally abundant glutamatergic innervation, which may be due to an arrest in the normal developmental process of synaptic elimination. In the anterior temporal cortex and hippocampus there is evidence of an asymmetric loss of glutamate terminals, and of reduced GABA function, which may be secondary to the glutamatergic deficit. Glutamate cell body markers are spared in the temporal lobe; we argue that the loss of glutamate uptake sites may reflect the loss of an extrinsic glutamatergic innervation of the polar temporal cortex which arises from the frontal cortex. These fronto-temporal projections may be vulnerable because they arise from a cytoarchitecture which has not been stabilized by remodelling during early post-natal life. There have been several therapeutic studies of drugs with actions on brain glutamate systems. Based on the glutamate deficiency theories, one approach has been to enhance glutamatergic function using agonists of the N-methyl-D-aspartate-linked glycine site. However, there are no clear therapeutic effects, and some studies report aggravation of positive symptoms. This might be expected if, as part of our post-mortem studies suggested, there is excess glutamatergic innervation in some brain regions in schizophrenia. There is neuropsychological evidence that frontal abnormalities in schizophrenia may be genetically determined. We found that first degree relatives of schizophrenic patients were selectively impaired in tests of frontal lobe function, whereas both frontal and temporal function is impaired in patients We conclude that the genetic predisposition to schizophrenia involves impaired frontal lobe function. Psychotic symptoms develop only when a second process results in a loss of fronto-temporal projections and leads to temporal lobe dysfunction.

Provocation, acute alcohol intoxication, cognitive performance, and aggression.

This study investigated the relationships between provocation, acute alcohol intoxication, impaired frontal-lobe function, and aggressive behavior. The authors ranked 114 men according to their performance on two neuropsychological tests associated with frontal-lobe function. Forty-eight men (24 with scores in the upper and 24 with scores in the lower performance quartiles) participated in the full study. Half completed and aggression task while intoxicated, the remainder while sober. Aggression was defined as shock intensity delivered to a sham opponent. Shock intensity significantly increased as a main effect of provocation, alcohol intoxication, and lower cognitive performance. Furthermore, provocation interacted significantly with test performance such that individuals in the lower cognitive performance quartile responded to increased provocation with heightened aggression.

Frontal lobe dementia and motor neuron disease.

Four patients are described, in whom a profound and rapidly progressive dementia occurred in association with clinical features of motor neuron disease. The pattern of dementia indicated impaired frontal lobe function, confirmed by reduced tracer uptake in the frontal lobes on single photon emission computed tomography (SPECT). Pathological examination of the brains of two patients revealed frontal-lobe atrophy, with mild gliosis and spongiform change. The spinal cord changes were consistent with motor neuron disease. The clinical picture and pathological findings resembled those of dementia of frontal-lobe type and were distinct from those of Alzheimer's disease. The findings have implications for the understanding of the spectrum of non-Alzheimer forms of primary degenerative dementia.

Topography of P300 response to target and novel stimuli in schizophrenic patients

To study frontal brain activity we measured event-related potentials (ERPs) to auditory target and novel stimuli in nine schizophrenic patients, five affective controls, and 13 normals. We predicted that schizophrenics, because of impaired frontal lobe function, would not show as much frontal augmentation of the P3 component to infrequent taskirrelevant novel stimuli as would normal subjects. Subjects were instructed to respond (finger lift) to infrequently occurring (10%) target tones (TS) while ignoring frequently occurring (80%) nontarget tones and infrequently occurring (10%) random electronic noise (NS). Ten channel EEG was collected until 30 correct and artifact-free trials to TS and NS were acquired. After transformation to average reference, the peak global field power between 276 and 450 milliseconds after stimulus onset was used to identify P300 latency. Potentials at this latency were compared across groups by repeated measures ANOVA. In agreement with previous studies, maximum positivity to NS shifted anteriorly relative to TS (p < .04). The topography of the P300 to NS varied with diagnosis (p < .007). The largest differences occurred at Cz, where the response to NS was larger than to TS across groups (p = .0003), but with smaller differences in schizophrenics (group x condition, p < .02). In fact, schizophrenics produced the shallowest potential maps (p < .04) and higher positivity in frontal relative to central leads (p < .05). Medicated schizophrenics (N = 5) differed from unmedicated schizophrenics (N = 4) only in prolonged latency (p = .002); there were no other latency differences between groups. These preliminary findings suggest a link between abnormalities of arousal and selective attention with frontal cortex functioning in schizophrenic patients.