Processing speed is correlated with cerebral health markers in the frontal lobes as quantified by neuroimaging.

We explored relationships between decline in cognitive processing speed (CPS) and change in frontal lobe MRI/MRS-based indices of cerebral integrity in 38 healthy adults (age 57-90 years). CPS was assessed using a battery of four timed neuropsychological tests: Grooved Pegboard, Coding, Symbol Digit Modalities Test and Category Fluency (Fruits and Furniture). The neuropsychological tests were factor analyzed to extract two components of CPS: psychomotor (PM) and psychophysical (PP). MRI-based indices of cerebral integrity included three cortical measurements per hemisphere (GM thickness, intergyral and sulcal spans) and two subcortical indices (fractional anisotropy (FA), measured using track-based spatial statistics (TBSS), and the volume of hyperintense WM (HWM)). MRS indices included levels of choline-containing compounds (GPC+PC), phosphocreatine plus creatine (PCr+Cr), and N-acetylaspartate (NAA), measured bilaterally in the frontal WM bundles. A substantial fraction of the variance in the PM-CPS (58%) was attributed to atrophic changes in frontal WM, observed as increases in sulcal span, declines in FA values and reductions in concentrations of NAA and choline-containing compounds. A smaller proportion (20%) of variance in the PP-CPS could be explained by bilateral increases in frontal sulcal span and increases in HWM volumes.

Loss of cerebral white matter structural integrity tracks the gray matter metabolic decline in normal aging.

Relationships between structural MRI-based markers of declining cerebral integrity, and regional PET measurements of (18)FDG uptake have not been studied well in normal aging. In this manuscript we relate changes in cerebral morphology to regional cerebral glucose uptake for 14 major cortical areas in 19 healthy older individuals (age 59-92 years). Measurements of cerebral integrity included gray matter (GM) thickness, sulcal and intergyral spans, fractional anisotropy (FA) of water diffusion and volume of hyperintense WM (HWM) lesions. (18)FDG-PET measurements were converted to standard uptake values and corrected for partial volume artifact. Following this, cortical FDG uptake was significantly correlated with several indices of WM integrity that we previously observed to be sensitive to cognitive decline in executive function, including intergyral span and HWM volumes. Our findings suggest that the age-related decline in white matter integrity, observed as increases in HWM lesions, intergyral spans and reduction in FA, correlated with a decline in the global and regional cerebral glucose uptake. Our findings support the emerging consensus that WM integrity indices are sensitive predictors of declining cerebral health in normal aging. Specifically, age-related WM degradation in the thinly myelinated association tracts appears to track the decreases in global and regional rates of glucose uptake.

Relationship between white matter fractional anisotropy and other indices of cerebral health in normal aging: tract-based spatial statistics study of aging.

White matter (WM) fractional anisotropy (FA) is thought to be related to WM integrity and decline in FA is often used as an index of decreasing WM health. However, the relationship of FA to other structural indices of cerebral health has not been well studied. We hypothesized that the decline in WM health will be associated with changes in several other indices of cerebral health. In this manuscript we studied the correlation between whole-brain/hemispheric/corpus callosum FA and gray matter (GM) thickness, sulcal span, and the volume of T2-hyperintense WM in a group of 31 healthy aging individuals (12 males/19 females) aged 57-82 years old. Individual subjects' FA measures were calculated from diffusion tracing imaging (DTI) data using tract-based spatial statistics--an approach specifically designed and validated for voxel-wise multi-subject FA analysis. Age-controlled correlation analysis showed that whole-brain average FA values were significantly and positively correlated with the subject's average GM thickness and negatively correlated with hyperintense WM volume. Intra-hemispheric correlations between FA and other measures of cerebral health had generally greater effect sizes than inter-hemispheric correction, with correlation between left FA and left GM thickness being the most significant (r=0.6, p<0.01). Regional analysis of FA values showed that late-myelinating fiber tracts of the genu of corpus callosum had higher association with other cerebral health indices. These data are consistent with the hypothesis that late-myelinating regions of the brain bear the brunt of age-related degenerative changes.

Severe dysosmia is specifically associated with Alzheimer-like memory deficits in nondemented elderly retirees.

OBJECTIVES: To determine whether or not (1) impaired olfactory function is associated with impaired memory on neuropsychological testing in healthy retirees, and if so then (2) whether memory impairment is most consistent with a mesiotemporal rather than frontal system disorder. METHODS: 173 independent residents of a continuing care retirement community were studied. Subjects completed the University of Pennsylvania Smell Identification Test (UPSIT) and a battery of both general and specific cognitive measures that included the Mini-Mental State Examination (MMSE) and the Executive Interview (EXIT25). Subjects were examined twice over 3 years. RESULTS: UPSIT performance was normal in 21% and in the 'anosmic' range in 25% of subjects. Anosmic UPSIT performance was associated with significantly worse performance on all cognitive tests. However, only short-term verbal memory was independently associated with UPSIT-defined anosmia. This association remained significant after adjusting for the other cognitive and sociodemographic variables. The memory deficits of anosmic subjects were qualitatively consistent with a cortical type (type 1) dementing illness such as Alzheimer's disease (AD). Over time, UPSIT-defined 'anosmic' cases suffered significantly greater declines on both the MMSE and the EXIT25, independently of baseline age, gender and MMSE score. CONCLUSIONS: Impaired odor identification in individuals without overt dementia is associated with an AD-like memory impairment and an increased rate of cognitive decline. The comorbid association of these deficits is consistent with the known hierarchical spread of preclinical AD pathology and may be a specific indicator of future clinical AD dementia.

Frontal MRI findings associated with impairment on the Executive Interview (EXIT25).

We examined the association between the Executive Interview (EXIT25), a bedside measure of executive control, and regional magnetic resonance imaging (MRI) pathology among 52 consecutive geriatric patients presenting to a university dementia assessment clinic. Left frontal (p < .002), left medial (p < .03), right frontal (p < .02), and right medial (p < .02) cortical lesions significantly worsened EXIT25 scores, even after adjusting for age, global cognitive impairment (on the Mini-Mental State Examination), and the severity of cortical dementia on the Qualitative Evaluation of Dementia [QED]. The EXIT25's associations with right hemisphere lesions did not persist after adjusting for left frontal lesions. Left posterior lesions did not significantly affect the EXIT25. Similarly, left frontal circuit pathology worsened EXIT25 scores (p < .05). Pathology in left anterior subcortical structures showed a trend (p = .052). EXIT25 scores were not affected by right subcortical pathology, nor by pathology in either hippocampus. We conclude that the EXIT25 is specifically affected by frontal system MRI lesions, particularly on the left. This conclusion is consistent with earlier functional neuroimaging studies associating EXIT25 performance with left mesiofrontal perfusion.

Executive cognitive impairment: a novel perspective on dementia.

In 1994 the American Psychiatric Association added impairment of executive control functions (ECF) to its list of cognitive domains that should be considered in the assessment of dementia. This recommendation has not been widely implemented. None the less, there is growing evidence that ECF impairment is common, strongly associated with disability and functional decline, and not well detected by traditional dementia screening tests. This article reviews the implications of ECF for the epidemiology of dementia. The total number of dementia cases may be much greater than previously thought and we are likely to be selectively missing cases with reversible causes of ECF impairment.

The use of herbal alternative medicines in neuropsychiatry. A report of the ANPA Committee on Research.

Growing numbers of people throughout the United States (40% in 1998) are using various forms of alternative therapies. A MEDLINE literature search of journals from the past three decades and an Internet database query were performed to determine the types and frequency of alternative therapies used, with special attention given to the herbal medicines used in neuropsychiatric disorders. Clinical effects, mechanisms of action, interactions, and adverse reactions of the herbal treatments are detailed. Objective controlled trials will be needed to establish safety and efficacy of herbal supplements. Knowledge of the properties of these therapies can improve the care of neuropsychiatric patients.

Correlates of disability among elderly retirees with "subclinical" cognitive impairment.

BACKGROUND: We assessed the effects of impaired Executive Control Function (ECF) on Instrumental Activities of Daily Living (IADL) and level of care among noninstitutionalized elderly retirees with "subclinical" cognitive impairment. METHODS: Subjects (N = 561; age 78.2 +/- 5.0 years) were residents of a single, 1,500 bed, continuing care retirement community. Subjects were examined for cognitive impairment using the Executive Interview (EXIT25), Mini-Mental State Examination (MMSE), and an executive clock-drawing task (CLOX). The CLOX is divided into executively sensitive (CLOX 1) and simple constructional (CLOX2) subtests. RESULTS: Residents in congregate high-rises (n = 301) differed significantly from those in independent-living apartments (n = 260) with respect to age, gender, percent living alone, EXIT25, CLOX1, MMSE, and CLOX2 scores (all p < .03). Only differences in ECF measures persisted after adjusting for age and living alone (p < .004). The EXIT25 (p < .006) and CLOX2 (p = .02) were associated with the use of prostheses. The differences in EXIT25 scores persisted after adjusting for level and living alone (p = .01). All instruments distinguished residents with impairment in IADLs. However, only CLOX2 (p < .001), EXIT25 (p < .001), and age (p < .001) made significant independent contributions. CONCLUSIONS: ECF has statistically significant effects on level of care and IADL impairment, even among noninstitutionalized retirees. This emergent disability is not well detected by traditional global cognitive measures. Evaluation and treatment may be delayed unless ECF measures are employed.

Executive control function: a rational basis for the diagnosis of vascular dementia.

Problems with diagnostic criteria for vascular dementia (VaD) stem from the inadequacy of the current dementia concept, a paradigm based on amnestic and other cortical deficits typical of Alzheimer disease (AD). However, most cases of VaD are due to subcortical lesions such as Binswanger-type periventricular white matter ischemia, or strokes causing decreased frontal activation and diaschisis-mediated cerebral hypoperfusion. We propose a new definition of dementia based on executive dysfunction and a formal assessment of executive control functions (ECF) for the diagnosis of VaD. The instruments proposed are the rapid screening executive clock-drawing task (CLOX; Royall et al. J Neurol Neurosurg Psychiatry 1998;64:588-94), and the more comprehensive Executive Interview Test (EXIT25; Royall et al. J Am Geriatr Soc 1992;40:122-6). Extensive application of these tests in elderly subjects in retirement communities has shown that both are brief, simple to administer, and more sensitive case-finding tools for cognitively impaired individuals than the Mini-Mental State Examination (MMSE). These three tests (CLOX, EXIT25, MMSE) accurately separate nondemented subjects from those with cortical or subcortical (frontal system) dementias. In addition, for controlled clinical trials of VaD, formal evaluation of motor and frontal sphincter functions--usually not considered part of the dementia syndrome--should also be included. Evaluation of gait and falls, timed-walk, manual dexterity, timed finger-tapping, and frontal bladder control (urge incontinence and nocturia) should improve determination of functional status and disability, and more accurately measure the effects of potential therapies.

Clock drawing is sensitive to executive control: a comparison of six methods.

We examined six clock-drawing task (CDT) scoring systems relative to the Executive Interview (EXIT25, a measure of Executive Control Function [ECF]) and the Mini-Mental State Exam (MMSE). Subjects included n = 33 National Institute of Neurological, Communicative Disorders, and Stroke "probable" Alzheimer's disease (AD) cases and n = 52 independent living controls. AD cases and controls differed on the EXIT25, MMSE, and all CDTs. All CDTs were significantly correlated with the EXIT25 (ranging from r = .56 to r = .78). These associations generally persisted after adjusting for Age, Education, and MMSE scores. In backwards stepwise linear multivariate regression models, only CLOX: An Executive Clock-Drawing Task scores contribute significantly to EXIT25 scores (R2 = .68) and MMSE scores (R2 = .72). Clock drawing draws upon both executive and general cognitive resources. CLOX explains incrementally more variance in ECF than other CDTs.

Frontal systems impairment in major depression.

Recent studies point to the importance of frontal systems in the control of complex behavior. Because major depression affects the same systems the considerable overlap between some so-called "depressive symptoms" and the behavioral sequelae of frontal lobe brain damage can be explained. In other mental disorders, functional outcomes are closely related to frontal system impairment. Frontal deficits, rather than mood disturbance, may explain the disability of depressed patients. This should cause doctors to reconsider their approach to depression. Treatment for the cognitive aspects of depression may be needed to ensure improvement in functional domains.

Pharmacologic efficacy in neuropsychiatry: a review of placebo-controlled treatment trials. A report of the ANPA Committee on Research.

Psychiatric disorders frequently compound the disability and complicate the management of neurologic conditions. These disorders result in increased morbidity for the person afflicted, stress for the caregiver, and financial burden. This study reviews the randomized double-blind placebo-controlled pharmacologic treatment trials of psychosis, depression, anxiety, and agitation in neurologic conditions from 1966 to 1998. Ten studies involving psychosis, 13 involving depression, and 20 involving anxiety-agitation meeting the committee's criteria were identified. Relatively few randomized double-blind placebo-controlled pharmacologic treatment trials of psychiatric disorders complicating neurologic disease have been conducted. These trials do not strongly support one specific pharmacologic approach to treatment. Further study of newer psychotropic agents, augmentation strategies, and novel use of other agents may help improve the treatment of psychiatric disorders observed in patients with neurologic disease.

Oxidative stress in smokers supplemented with vitamin C.

The ability of vitamin C supplement to influence lipid peroxidation and pulmonary function tests in healthy smokers was investigated. In this randomized double blind controlled trail, 56 smokers (S) received either 500 mg of vitamin C (C) or placebo (P) daily for 4 weeks. All completed the trial. Both groups were comparable and the number of cigarettes smoked were C: 14.2 +/- 1.8 and P: 18.3 +/- 2.0 pack-years. Plasma vitamin C concentrations increased significantly (p < 0.005) only in the group supplemented with vitamin C. Lipid peroxidation measured by breath pentane output (BPO) (C: 7.5 +/- 1.4 vs P: 7.0 +/- 1.3 pmol.kg-1.min-1) and plasma HPLC-separated malondialdehyde (MDA) (C: 0.58 +/- 0.05 vs P: 0.47 +/- 0.05 nmol.ml-1) were not significantly different between the 2 groups at baseline and did not change after four weeks of vitamin C supplementation (BPO: C: 5.3 +/- 0.9 vs P: 5.5 +/- 0.9 pmol.kg-1.min-1; HPLC-MDA: C: 0.50 +/- 0.07 vs P: 0.42 +/- 0.07 nmol.ml-1). No changes were detected in pulmonary function tests even in heavy smokers. Therefore, 4 week supplementation with 500 mg of vitamin C did not change lipid peroxidation indices and had no effect on pulmonary function tests.

Executive dyscontrol: an important factor affecting the level of care received by older retirees.

OBJECTIVES: To examine the relative contributions of Executive Control Function (ECF), general cognition, mood, problem behavior, physical disability, demographic variables, and the number of prescribed medications to the level of care received by older retirees. DESIGN: Multivariate regression and discriminant modeling. SETTING: A single Continuing Care Retirement Community (CCRC) in San Antonio, Texas. PARTICIPANTS: A total of 107 older retirees (mean age = 83.7+/-7.2 years), including 17 community-dwelling, well, older controls and 90 CCRC residents. CCRC subjects represented a convenience sample of consecutive referrals for geropsychiatric assessment. Sixty-one subjects resided at a noninstitutionalized level of care, and 46 were institutionalized. MEASUREMENTS: Tests of ECF (the Executive Interview (EXIT25)), general cognition (the Mini-Mental State Examination (MMSE)), mood (the Geriatric Depression Scale short-form (sGDS)), problem behavior (the Nursing Home Behavior Problem Scale (NHBPS)), physical disability (the Cumulative Illness Rating Scale (CIRS)), age, gender, years of education, and the number of prescribed medications were studied. RESULTS: All variables except gender and education varied significantly across level of care. Four variables made significant independent contributions; EXIT25 score (r2 = .48, P< .001), medication usage (partial r2 = .11, P<.001), sGDS score (partial r2 = .06, P = .001), and problem behavior (partial NHBPS r2 = .04, P<.04). These variables accounted for 69% of the total variance in level of care (R2 = .69; F (df 7,99) = 32.1, P<.001). A discriminant model based on the number of prescribed medications, EXIT25, sGDS, and NHBPS scores classified 83.2% of cases correctly (Wilke's lambda = .50, F(5,101) = 20.1; P<.001). The MMSE enters but fails to contribute significantly, independent of the other variables. Age and CIRS scores fail to enter. CONCLUSIONS: Cognitive (particularly ECF) impairment contributes most to the observed variance in level of care received by older retirees in this CCRC. In contrast, markers of general cognition, depression, and physical illness contributed relatively little additional variance. ECF is not detected well by traditional cognitive measures and must be sought by specific tests. Further study is needed to replicate these findings in other populations.

Neuropsychiatric correlates and treatment of lenticulostriatal diseases: a review of the literature and overview of research opportunities in Huntington's, Wilson's, and Fahr's diseases. A report of the ANPA Committee on Research. American Neuropsychiatric Association.

This report reviews clinical neuropsychiatric findings and opportunities for research in Huntington's, Wilson's, and Fahr's diseases. Consistent, systematic methodology is lacking among neuropsychiatric studies in these lenticulostriatal diseases. Systematic cross-sectional and longitudinal assessments are needed to ascertain the prevalence of psychiatric disorders as a function of disease course. Preliminary synthesis of existing data suggests the following heuristic relationships in these diseases: depression with parkinsonian states; personality changes with caudate or putamen disease; psychosis, impulsivity, and sexual disorders with caudate disease; dementia and mania with caudate and pallidal diseases; and compulsions with pallidal disease. Correlation of neuropsychiatric findings with disease stage, clinical signs, and radiologic, metabolic, physiologic, and pathologic markers of disease will add to our understanding of these conditions.

CLOX: an executive clock drawing task.

OBJECTIVE: To describe a clock drawing task (CLOX) designed to elicit executive impairment and discriminate it from non-executive constructional failure. SUBJECTS: 90 elderly subjects were studied (45 elderly and well persons from the independent living apartments of a continuing care retirement community and 45 patients with probable Alzheimer's disease). The clock drawing performance of elderly patients was compared with that of 62 young adult controls. METHODS: Subjects received the CLOX, an executive test (EXIT25), and the mini mental state examination (MMSE). The CLOX is divided into an unprompted task that is sensitive to executive control (CLOX1) and a copied version that is not (CLOX2). Between rater reliability (27 subjects) was high for both subtests. RESULTS: In elderly subjects, CLOX subscores correlated strongly with cognitive severity (CLOX1: r=-0.83 v the EXIT25; CLOX2: r=0.85 v the MMSE). EXIT25 and MMSE scores predicted CLOX1 scores independently of age or education (F(4,82)=50.7, p<0.001; R2=0.71). The EXIT25 accounted for 68% of CLOX1 variance. Only the MMSE significantly contributed to CLOX2 scores (F(4,72)= 57.2, p<0.001; R2=0.74). CLOX subscales discriminated between patients with Alzheimer's disease and elderly controls (83.1% of cases correctly classified; Wilkes' lambda=0.48, p<0.001), and between Alzheimer's disease subgroups with and without constructional impairment (91.9% of cases correctly classified; Wilkes' lambda=0.31, p<0.001). CONCLUSIONS: The CLOX is an internally consistent measure that is easy to administer and displays good inter-rater reliability. It is strongly associated with cognitive test scores. The pattern of CLOX failures may discriminate clinical dementia subgroups.