Donald R. Royall

Alzheimer Disease as a Vascular Disorder: Nosological Evidence

Background— The main stumbling block in the clinical management and in the search for a cure of Alzheimer disease (AD) is that the cause of this disorder has remained uncertain until now. Summary of Review— Evidence that sporadic (nongenetic) AD is primarily a vascular rather than a neurodegenerative disorder is reviewed. This conclusion is based on the following evidence: (1) epidemiological studies showing that practically all risk factors for AD reported thus far have a vascular component that reduces cerebral perfusion; (2) risk factor association between AD and vascular dementia (VaD); (3) improvement of cerebral perfusion obtained from most pharmacotherapy used to reduce the symptoms or progression of AD; (4) detection of regional cerebral hypoperfusion with the use of neuroimaging techniques to preclinically identify AD candidates; (5) presence of regional brain microvascular abnormalities before cognitive and neurodegenerative changes; (6) common overlap of clinical AD and VaD cognitive symptoms; ...

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;R 2 =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;R 2 =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.

Declining Executive Control in Normal Aging Predicts Change in Functional Status: The Freedom House Study

Objectives: To assess the contribution of executive control function (ECF) to functional status.

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.

Executive control mediates memory's association with change in instrumental activities of daily living: the Freedom House Study.

Objectives: To assess the relative independent contribution of changes in executive control function (ECF) and memory to changes in functional status.

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.

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.

Relationship among neuroimaging indices of cerebral health during normal aging

Sensitive measures of brain aging show great promise for gauging factors that affect aging and degenerative processes, such as risk genes or therapy. Here we examined age‐related trends for three indices of cerebral health: gyral gray matter (GM) thickness, dilation of sulcal spaces with CSF, and the volume of T2‐hyperintense white matter (HWM) lesions. The study involved 31 healthy adults age 57–82 years old. Measurements of average GM thickness, average sulcal span and HWM volume were performed using high‐resolution 3D T1‐ and T2‐weighted brain MR images. Age‐related trends for the three cerebral health indices were consistent with previously published work though the analysis of their covariance led to a previously unreported relationship. Simultaneous multiple regression found that dilation of cortical sulci were primarily (t = 2.59, P < 0.01) related to the increases in HWM volume and secondarily related (t = −2.51, P < 0.01) to the reductions of the cortical GM thickness. The are‐corrected correlation between reduction in GM thickness and increases in HWM volume, was not significant (P = 0.34). These findings are of interest in designing quantitative measures of brain aging for monitoring individual patients and in large‐scale clinical trials. Hum Brain Mapp 2008.

Executive Control and the Comprehension of Medical Information by Elderly Retirees

This study examined the independent contributions of executive control function, general cognition, age, education, and medication usage to the comprehension of medical information. Randomly selected elderly retirees (N = 105) more than 70 years of age completed the Executive Interview (EXIT25), the Mini-Mental State Exam (MMSE), and the Hopkins Competency Assessment Test (HCAT). Cognitive measures were stronger predictors of HCAT scores than age, education, or number of prescribed medications. A discriminant model based on EXIT25 and MMSE scores correctly classified 91% of subjects relative to their HCAT scores. It was concluded that executive impairment is strongly associated with impaired comprehension of medical information. As many as 88% of probable Alzheimers disease patients, 69% of institutionalized elderly retirees, and 49% of noninstitutionalized retirees may be impaired in their ability to comprehend medical information, even when it has been presented well below their educational level.

Depression, disability and intermediate pathways: a review of longitudinal studies in elders.

Cross-sectional studies demonstrate depression is associated with disability in elders. These studies also report that disability in depressed elders is associated with greater medical illness burden, cognitive impairment, and behavioral changes. Only longitudinal studies, however, can determine the impact of depression and its comorbidities on functional decline. This review summarizes the findings of 20 longitudinal studies examining the relationship between baseline or incident depression and functional decline. However, the mediational effects of potential risk factors identified by cross-sectional studies cannot be derived from the current literature. We propose a mediational effects model for future longitudinal studies, incorporating measures sensitive to both mood symptoms and the medical, cognitive, and behavioral comorbidities of depression to better understand the impact of each on functional decline and to focus future clinical interventions.