Clinical differentiation of primary degenerative and multi-infarct dementia: a critical review of the evidence. Part I: Clinical studies.

For patient care and for research purposes there is an obvious need for a valid and reliable set of clinical criteria to distinguish antemortem between primary degenerative dementia (PDD) and multi-infarct dementia (MID). To this end, specific diagnostic criteria for each have been promulgated in the official nomenclature, and a rating scale devised to differentiate these disorders is in wide use. These efforts suggest a diagnostic capability that is not, however, well supported by the literature. This critical analysis of representative clinical studies and articles published over the past two decades reveals important drawbacks in methodologic approaches and interpretation of data which seriously undermine confidence in making the clinical distinction between PDD and MID.

Clinical differentiation of primary degenerative and multi-infarct dementia: a critical review of the evidence. Part II: Pathological studies.

A critical examination of representative pathological studies published over the past four decades reveals that this literature fails to provide sufficient support for the antemortem differentiation of primary degenerative dementia (PDD) from multi-infarct dementia (MID) on the basis of clinical criteria. Similar conclusions with respect to clinical studies and articles are presented in Part I of this overview. Among the difficulties commonly encountered in the literature are sampling bias, retrospective design, nonblind assessments, inadequate sample size, failure to consider overlap (i.e., mixed cases), absence of pathological verification in the clinical studies and post hoc reasoning. The necessity to assure that one is dealing with a case of PDD as opposed to some other dementing process is self-evident. However, these reviews show that this capability has not been adequately established with respect to the differential diagnosis of PDD and MID; the evidence to date indicates that the clinical diagnosis of MID, in particular, should be made with caution until more conclusive methods become available.

Major depression in the elderly: DSM-III criteria and the dexamethasone suppression test as predictors of treatment response.

Twenty-seven elderly individuals with DSM-III diagnoses of major depression who demonstrated a nonsuppressor response to the dexamethasone suppression test had higher pretreatment levels of mood disturbance, required higher dosages of antidepressant medication, and had poorer responses to treatment than 17 clinically similar individuals with a suppressor response. However, when data on the outcomes of suppressors and nonsuppressors were combined, over half of the entire group sustained significant improvement, which supports the practical value of DSM-III criteria for depression in the elderly.

Predictors of cognitive change in middle-aged and older adults with memory loss.

OBJECTIVE: Previous longitudinal studies of age-related memory loss have focused on objective neuropsychological measures that predict subsequent cognitive change, yet brain metabolic function, self-perception of memory loss, and other measures may also be sensitive indicators of cognitive change. To determine such baseline predictors of change, the authors made longitudinal assessments of middle-aged and older adults with memory loss. METHOD: Forty-two persons (mean age = 60 years, range = 43-81) with memory complaints received comprehensive baseline assessments, including subjective neuropsychological measures, objective measures of visual-spatial memory (the Benton Visual Retention Test) and verbal memory (the Buschke-Fuld Selective Reminding Test), and positron emission tomography scans to determine neocortical glucose metabolism. At an average follow-up of 3 years, the objective neuropsychological measures were again used to quantify the degree of cognitive change. RESULTS: Multiple regression analyses indicated that parietal asymmetry, sex of the subject, and baseline visual-spatial memory score were significant predictors of change in visual-spatial memory; level of education and baseline verbal memory score predicted change in verbal memory. Other neocortical asymmetry scores, age, family history of Alzheimer's disease, cerebral atrophy, and self-ratings of use of mnemonics were not significant predictors of change. CONCLUSIONS: Measures of cerebral metabolism, objective memory performance, sex, and education may predict subsequent cognitive change in middle-aged and older persons with memory loss. Also, the parietal asymmetry found in persons with questionable dementia that progresses to probable Alzheimer's disease may be present very early in the course of age-related cognitive decline.

Nutritional status and cognitive functioning in a normally aging sample: a 6-y reassessment.

Associations between nutritional status and cognitive performance were examined in 137 elderly (aged 66-90 y) community residents. Participants were well-educated, adequately nourished, and free of significant cognitive impairment. Performance on cognitive tests in 1986 was related to both past (1980) and concurrent (1986) nutritional status. Several significant associations (P < 0.05) were observed between cognition and concurrent vitamin status, including better abstraction performance with higher biochemical status and dietary intake of thiamine, riboflavin, niacin, and folate (rs = 0.19-0.29) and better visuospatial performance with higher plasma ascorbate (r = 0.22). Concurrent dietary protein in 1986 correlated significantly (rs = 0.25-0.26) with memory scores, and serum albumin or transferrin with memory, visuospatial, or abstraction scores (rs = 0.18-0.22). Higher past intake of vitamins E, A, B-6, and B-12 was related to better performance on visuospatial recall and/or abstraction tests (rs = 0.19-0.28). Use of self-selected vitamin supplements was associated with better performance on a difficult visuospatial test and an abstraction test. Although associations were relatively weak in this well-nourished and cognitively intact sample, the pattern of outcomes suggests some direction for further research on cognition-nutrition associations in aging.

Clinical, neuroimaging, and environmental risk differences in monozygotic female twins appearing discordant for dementia of the Alzheimer type.

OBJECTIVE: The study of monozygotic twins can elucidate possible environmental causes for a disease in genetically identical subjects. To this end, we studied a pair of monozygotic female twins appearing discordant for dementia of the Alzheimer type (DAT). DESIGN: Clinical and neuroimaging findings were compared in terms of potential environmental risk factors. SETTING: University referral center. PARTICIPANTS: An 81-year-old female monozygotic twin pair. OUTCOME MEASURES: Clinical assessments, standardized rating scales, and brain imaging studies, including magnetic resonance imaging, positron emission tomography, and electroencephalography, were performed. Neuropsychological tests were performed initially and after 1 year. RESULTS: Although DAT was confirmed clinically in only one twin, neuropsychological and brain imaging studies suggested that the unaffected twin may be developing the prodrome of DAT. The twins' varied life histories suggest that environmental risk factors may contribute to apparent discordance for DAT and possible delay in disease onset for the currently nondemented twin. CONCLUSIONS: These results suggest that both genetic and nongenetic factors influence disease onset and expression. Moreover, review of previous reports of monozygotic twin pairs concordant or discordant for Alzheimer's disease, with adequate family history data, suggest a pattern indicating interactions among age at dementia onset, sex, and familiarity. Such patterns point to hypotheses regarding neurobiologically meaningful Alzheimer's disease subgroups.

Acute response to methylphenidate as a predictor of outcome of treatment with TCAs in the elderly.

Acute response to a single-dose, nonblind administration of methylphenidate 20 mg predicted outcome of treatment with desipramine in 42 elderly depressed inpatients. Treatment outcome was not predicted by the methylphenidate challenge in 29 patients who received amitriptyline. These findings are consistent with Maas' biogenic amine hypothesis and are encouraging with respect to the clinical utility of the methylphenidate challenge in geriatric depression.

Early detection of Alzheimer's disease by combining apolipoprotein E and neuroimaging.

New treatments for Alzheimer's disease (AD) are more likely to slow or halt disease progression rather than to reverse existing neuronal damage. Identifying persons with mild cognitive complaints who are at risk for AD will allow investigators to apply anti-dementia treatments before extensive brain damage develops. The discovery of the apolipoprotein E epsilon 4 allele (APOE epsilon 4) as a major risk factor for AD offers promise of assisting in early detection and prediction of Alzheimer's disease, particularly when genetic assessments are combined with other biomarkers such as neuroimaging. Studies of relatives at risk for familial AD using neuroimaging (positron emission tomography [PET]) and genetic assessments of APOE suggest that at-risk relatives with APOE epsilon 4 have lower parietal metabolism than those without APOE epsilon 4. Additional techniques that might increase sensitivity and specificity include longitudinal assessment of clinical and brain functional change, pharmacological challenges of short-acting anticholinergic agents, and memory activation paradigms during functional scanning. Such strategies should eventually assist in early detection of AD and in vivo therapeutic monitoring of brain function during experimental anti-dementia treatment trials.

Cognitive impairment in late-life depression: clinical correlates and treatment implications.

Elderly depressed inpatients with high vs. low scores on a quantitative mental status examination (the Mini-Mental State (MMS)) were compared with regard to demographic and clinical characteristics, treatment and short-term response, and functional status at 2-year follow-up. Low-MMS patients were less well educated and more likely to be delusional, anxious, and globally impaired than high-MMS patients. The two groups responded equally well to treatment, but the low-MMS group required a lengthier hospital stay and greater use of neuroleptic medications. The two groups also had similar long-term outcomes, although greater attrition was observed among cognitively impaired subjects.

Cognition and depression in a cohort of aging men: results from the Western Collaborative Group Study.

Relationships between cognitive performance and self-ratings of depression on the Center for Epidemiologic Studies Depression scale (CES-D; L.S. Radloff, 1977) were examined for 1,217 older men. After controlling for demographic variables and both objective and subjective measures of health, significant associations were observed between several CES-D variables and measures of cognitive mental status, memory, and psychomotor speed. The Well-Being factor of the CES-D was the most robust predictor of cognitive scores. Therefore, for older adults with generally favorable health and socioeconomic resources, there may be a link between positive affect and maintenance of cognitive effectiveness.

Clinical tests of memory in dementia, depression, and healthy aging.

In Study 1, carefully screened elderly adults with primary degenerative dementia or major depression were compared to healthy aged control subjects on three tests of learning and memory: the Benton Visual Retention Test, Inglis Paired-Associate Learning Test, and the Fuld Object-Memory Evaluation (OME). The sharpest distinction in performance among the groups was observed on the OME, and discriminant equations based on this test correctly classified a high percentage (greater than or equal to 90%) of participants. Study 2 applied the classification rules derived in the first investigation to an unselected series of geropsychiatry inpatients referred for neuropsychological evaluation. There was agreement between memory test classification and general categories of clinical discharge diagnosis (organic vs. functional) for 21 of 25 patients, and with status at follow-up approximately 18 months later. Predictive value computations suggested that the OME is more accurate in confirming true dementia than in detecting dementia syndromes associated with functional disorders.

Mood state and cerebral metabolism in persons with age-associated memory impairment.

People undergoing medical procedures sometimes experience feelings that may influence the results. In this study, we explore the relationship between changes in mood state self-ratings and cerebral glucose metabolism during positron emission tomography (PET) in persons with age-associated memory impairment (mean age 59.4 +/- 9.8 years). Brain regions of interest involved in both mood and memory were examined. Mood ratings of increased boredom correlated significantly with mesial temporal and parietal asymmetry and decreased parietal metabolism. Mood ratings of increased fatigue correlated with basal ganglia asymmetry and the right basal ganglia and left mesial temporal metabolism. These findings suggest that subjective mood state changes during PET may influence metabolism in brain regions implicated in emotion and memory function in people with age-related memory complaints.

Retrospective accounts of dementia symptoms: are they reliable?

Relatives of patients with dementia completed questionnaires about caregiver stress and patients' functional and psychiatric problems during an initial evaluation, at follow-up 4 to 17 months later, and retrospectively (i.e., based on recall of symptoms and behaviors at the initial assessment). Retrospective accounts correlated well with initial reports, particularly with larger scales including a wider range of alternative responses, but psychiatric symptoms were underreported in the retrospective accounts. Spouses tended to report lower levels of psychiatric symptoms than did younger relatives.

Relationship between 24-Hour Ambulatory Blood Pressure and Cognitive Function in Healthy Elderly People.

This study explored the relationship between cognitive function and blood pressure (BP) in 84 women and 64 men, aged 55-79. Assessments were made of casual BP, 24-hour ambulatory BP, and cognitive function. Participants had no evidence of any health disorders, were taking no medication, and were primarily normotensive. By means of principal components analysis, the number of variables was reduced to three BP components of Level, Wake Variability, and Sleep Variability and four cognitive components of Psychomotor Speed/Cognitive Flexibility, Attention, Verbal Memory, and Short-term/Working Memory. Elevated ambulatory BP (level and variability) was associated with difficulties in Attention and Short-term/Working Memory. The fact that increased risk of poorer cognitive function may be related to BP in an elderly population with relatively low BP means that even moderate elevations in BP may be cause for concern.

Methodological concerns: longitudinal studies of dementia.

Common methodological problems in longitudinal research on dementia are discussed, applying terms and constructs from the literature on normal aging. Critique of prevailing methods suggests that longitudinal studies of dementia could be improved by more extensive pilot examination of dependent measures and by more stringent control of instrumentation bias. The impact of attrition also needs to be more thoroughly evaluated before generalizations are stated about rates and patterns of decline in dementing illness.

Patterns of performance on the Fuld Object Memory Evaluation in elderly inpatients with depression or dementia.

The Fuld Object Memory Evaluation (Fuld, 1981) was administered to 80 elderly adults (aged 60 to 90 years) who were hospitalized for evaluation and treatment of primary degenerative dementia (PDD), other organic disorders (e.g., Parkinson's disease or multi-infarct dementia), or major depression. Although mean performance in each of the diagnostic groups was below normative levels reported by Fuld (1981), PDD patients performed significantly more poorly than those with depression or other organic disorders. Analysis of subscore patterns failed to support the hypothesis of a selective memory deficit in depression, and substantial overlap in scores was observed between the depressed group and patients with organic disorders other than PDD. Object Memory Evaluation performance was influenced by global mental status and secondary psychiatric diagnoses, but not by education, age, or physical health.

Cognitive function and prediction of dementia in old age.

Longitudinal changes in cognitive functioning were examined for a sample of aging twins, some of whom developed dementia while others did not. Individuals who were judged to be demented at a mean age of eighty-five years had achieved lower scores on most tests twenty years prior to diagnosis, and experienced greater declines in vocabulary and forward digit span over time, than those surviving to a comparable age without dementia. These trends were observed for individuals with mild, as well as moderate-to-severe, dementia and were unrelated to physical health status or premorbid activity patterns. It is suggested that dementing illness may develop very slowly, and that the likelihood of exhibiting clinically significant dementia may vary with premorbid intellectual level.

Cognitive changes in young-old adults: effect of family history of dementia.

Cognitive performance of 40 first-degree relatives of patients with probable Alzheimer disease was compared to that of 24 matched controls without a family history of dementia. Across a test-retest interval ranging from 1 to 6 years, relatives more often showed evidence of cognitive decline, and in multivariate analyses of memory and intelligence measures, relatives of patients with early-onset dementia (< 67 years) showed greater decline than controls or relatives of patients with late-onset dementia. All changes observed to date are in the subclinical range, and further follow-up will be needed to determine the reliability of change trajectories. However, the findings suggest that family history of dementia may be worthy of monitoring in research on normal cognitive aging.

Self-reports of memory problems in relatives of patients with probable Alzheimer's disease.

This study examined the relationship between subjective memory complaints and performance on tests of memory by relatives of patients with probable Alzheimer's disease (AD) and by older adults without a family history of dementia. Relatives of AD patients did not differ significantly from controls either in level of complaint or in performance on neuropsychological tests. However, among relatives of patients with early-onset AD, significant correlations were found between performance on memory tests and self-rated changes in everyday memory. These findings raise the possibility that relatives who have entered the age range in which their parents or siblings developed dementia symptoms are monitoring their memory performance more diligently than relatives of patients whose illness began at much later ages or persons who have no close relatives with AD.