Elisabeth Koss

Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members

The development of Alzheimers disease (AD) later in life may be reflective of environmental factors operating over the course of a lifetime. Educational and occupational attainments have been found to be protective against the development of the disease but participation in activities has received little attention. In a case-control study, we collected questionnaire data about 26 nonoccupational activities from ages 20 to 60. Participants included 193 people with probable or possible AD and 358 healthy control-group members. Activity patterns for intellectual, passive, and physical activities were classified by using an adaptation of a published scale in terms of “diversity” (total number of activities), “intensity” (hours per month), and “percentage intensity” (percentage of total activity hours devoted to each activity category). The control group was more active during midlife than the case group was for all three activity categories, even after controlling for age, gender, income adequacy, and education. The odds ratio for AD in those performing less than the mean value of activities was 3.85 (95% confidence interval: 2.65–5.58, P < 0.001). The increase in time devoted to intellectual activities from early adulthood (20–39) to middle adulthood (40–60) was associated with a significant decrease in the probability of membership in the case group. We conclude that diversity of activities and intensity of intellectual activities were reduced in patients with AD as compared with the control group. These findings may be because inactivity is a risk factor for the disease or because inactivity is a reflection of very early subclinical effects of the disease, or both.

Retrieval from semantic memory in Alzheimer-type dementia

Retrieval from semantic memory, measured by tasks requiring subjects to name items from a given category, was studied in mild Alzheimer-type dementia (Mild-ATD) subjects, moderate-to-severe Alzheimer-type dementia (MS-ATD) subjects, and normal controls. Semantic retrieval performance was shown to be highly sensitive to both the presence and the severity of ATD. Retrieval from both semantic categories and letter categories showed differences in the rate of production of correct responses between subject groups. These rate differences were not due to differences in accessibility of low-dominance semantic category members or low-frequency letter category members. An increase in errors as well as a decrease in correct responses contributed to the performance deficits of the ATD subjects. Furthermore, the pattern of errors changed from Mild- to MS-ATD. Qualitative as well as quantitative differences were also observed in the performance of Mild- versus MS-ATD groups on a third type of semantic retrieval task--the supermarket task. As performance of the ATD subjects declined on these semantic retrieval tasks, so did their performance on other tasks assessing primarily attention, language, and memory. The findings are discussed in terms of the progressive breakdown in both attentional and semantic memory functions which are associated with ATD.

Heterogeneous anterior‐posterior metabolic patterns in dementia of the Alzheimer type

The parietal-frontal distribution of reductions of regional cerebral metabolic rates for glucose (rCMRglc) was studied in 32 patients with mild to severe dementia of the Alzheimer type (DAT), using positron emission tomography and fluorodeoxyglucose, and was related to patterns of neuropsychological impairment. In moderate and severe DAT patients, one frontal association region, the premotor cortex, demonstrated significant metabolic reductions equivalent to reductions in the parietal association cortex, and the ratio of parietal to premotor rCMRglc had significantly greater variance than in controls. In moderately demented patients, parietal-premotor and parietal-prefrontal metabolic ratios correlated significantly with neuropsychological impairments. Disproportionate parietal hypometabolism was associated with more impairment of verbal comprehension, calculations, visuospatial construction, and immediate visuospatial memory span. Disproportionate frontal hypometabolism was associated with more impaired verbal fluency and attention. Longitudinal follow-up of 20 of the patients showed that parietal/frontal metabolic ratios and their correlated neuropsychological patterns were stable over time, as dementia severity worsened. These results indicate that in moderate to severe DAT patients, metabolic reductions in the premotor cortex are as severe as the reductions in the parietal association cortex. Moreover, the parietal-premotor distribution of metabolic reductions is variable and related to variable patterns of cognitive impairment.

Alzheimer's disease: Anterior-posterior and lateral hemispheric alterations in cortical glucose utilization

We performed dynamic positron emission tomographic studies with [18F]fluorodeoxyglucose in 17 subjects with presumed Alzheimers disease (AD) and 7 healthy aged subjects. Glucose metabolism was depressed by 27% in temporal-parietal cortex of the AD group, as compared to healthy aged controls. This focal impairment in temporal-parietal glucose use was found in all AD subjects. In addition, the AD group showed a striking lateral asymmetry of cortical metabolism not favoring either hemisphere, which has not been previously reported. Relationships between these focal changes and behavioral features of the illness were demonstrated. These results have important implications for the diagnosis and perhaps the etiology of Alzheimers disease.

Longitudinal studies of regional cerebral metabolism in Alzheimer's disease

Measurement of cerebral glucose metabolism in six patients with Alzheimers disease using positron emission tomography demonstrated that hypometabolism remained relatively more severe in parietal cortex than in frontal cortex over time. Lateral metabolic asymmetries were preserved in less severely involved brain regions, but were less stable in parietal cortex.

Regional cerebral glucose transport and utilization in Alzheimer's disease

We performed dynamic positron emission tomographic (PET) studies of glucose utilization, using (18F) 2-fluoro-2-deoxy-D-glucose (FDG), in patients with probable Alzheimers disease (AD) and healthy age-matched controls, to evaluate blood-brain-barrier glucose transport and glucose utilization rates in the disease. We found no significant differences in rate constants for glucose transport (k1 and k2) and phosphorylation (k3), nor for the vascular fraction (fv), between the 2 groups, although k3 and fv were relatively depressed in temporal cortex in AD. Absolute rates of glucose use were depressed in temporal and parietal cortex, and relative rCMRglc rates were lower in frontal, temporal, parietal, and occipital cortices. These data suggest that in AD bidirectional glucose transport is intact, and that temporal-parietal hypometabolism is present upon a background of widespread cortical metabolic impairment.

Delirium in Alzheimer Disease

Summary:Advanced age and dementia are well-known risk factors for delirium, and most studies of delirium have concentrated on hospitalized populations. We reviewed the records of 199 community-dwelling Alzheimer disease (AD) patients and identified 43 (22%) who had had episodes of delirium during their dementing illness. These patients were matched for age, gender, and disease duration to AD patients without previous episodes of delirium. Variables examined included causes of delirium, Mini-Mental State Examination scores, Clinical Dementia Rating scores, Blessed Activities of Daily Living (ADL) scores, years of education, neuropsychological performance, and incidence of behavioral symptoms on the Brief Psychiatric Rating Scale. In six of 198 (3%) patients delirium was an initial symptom of AD. Conditions associated with onset of delirium were urinary tract infections, stressful events, surgery, medical illnesses, and medications. No significant differences were found between groups on neuropsychological testing. Patients with previous episodes of delirium had worse ADL scores and higher disease-course incidences of hallucinations and paranoid delusions, mostly occurring during the delirious episode. We conclude that delirium is common in AD, but it is an unusual initial symptom and it occurs in diverse clinical settings. Measures of behavioral symptoms and ADLs are more likely to reflect the impact of delirium on clinical status than measures of cognition or stage of dementia.

Alzheimer Disease: Clinical and Biological Heterogeneity

The clinical and biological features of Alzheimer disease are not uniform in their expression; heterogeneity is evident in the diseases clinical, anatomic, and physiologic characteristics. The presence of considerable intersubject and intrasubject heterogeneity suggests that subtypes of the disease exist. We define subtypes of Alzheimer disease in regard to the behavioral features (for example, predominant right or left hemisphere, or symmetrical impairment), inheritance (familial or sporadic), dosage of chromosome 21 (presence of the Down syndrome), time course of progression, age of onset (presenile or senile), and presence or absence of motor deficit (myoclonus or signs of an extrapyramidal syndrome). Studies of regional cerebral glucose metabolism with positron emission tomography and [18-fluorine] fluorodeoxyglucose show focal alterations in glucose use, with cerebral metabolic asymmetries in patients with Alzheimer disease that are related to the nature of the cognitive deficit. Serial roentgenographic computed tomographic studies show heterogeneous rates of lateral ventricle enlargement in the disease that are related to rates of cognitive decline. Similar anatomic and physiologic abnormalities are also found in persons 45 years of age or older who have the Down syndrome. Furthermore, patients with Alzheimer disease who have extrapyramidal dysfunction or myoclonus are a distinct subgroup, with specific abnormalities of central monoamine markers of dopamine metabolism, serotonin metabolism, and the hydroxylation cofactor, biopterin. The concept of subtypes in Alzheimer disease serves as a model with which the interactions of genetic influences with environmental factors can be examined.

The Stroop Color-Word Test: Indicator of Dementia Severity

The Stroop color-word test was used to examine patterns of cognitive decline in Alzheimer-type dementia (ATD) and non-Alzheimer dementia. Slowing on color naming and word reading was observed, and was greater in moderate than in mild dementia subjects. However, error scores were unrelated to dementia type and severity. The Stroop interference effect, measured with reaction time, was high in individuals with mild ATD and mild non-Alzheimer dementia. In contrast, the more severely impaired ATD subjects showed less Stroop interference effect than mildly impaired subjects when the reaction time was adjusted for color naming performance. These findings are attributed to variation in speed-accuracy tradeoff for the patient groups due to differences in information processing deficits, linguistic impairment, and attitudes to errors. This study demonstrates the importance of partialling out underlying deficits for the understanding of complex cognitive processes in dementia.

Visuoconstructive performance and regional cerebral glucose metabolism in Alzheimer's disease.

The drawings of Alzheimers disease (AD) patients and elderly control subjects were rated on a number of specific performance scales, such as attention to configuration, attention to detail, and stimulus boundedness. AD patients showed significantly poorer performance than controls on most drawing scales, and the drawing measures were differentially affected by disease severity. Regional cerebral glucose metabolism (rCMRglc) was assessed via positron emission tomography (PET, with 18FDG) in a subgroup of the AD patients. Partial correlations of rCMRglc with drawing measures (age, sex, and education served as control variables) were conducted. Five out of eight of the drawing measures were significantly correlated (p less than .005) with rCMRglc in occipital and/or temporal-parietal regions, for both left and right hemispheres. Only one of the eight drawing measures, attention to detail, was significantly correlated with rCMRglc in both frontal and posterior regions of interest, again for both hemispheres. Overall dementia severity showed no significant correlations with rCMRglc in any of the regions. These findings are suggestive of a posterior-anterior differentiation, but no left-right hemisphere differentiation, in the relationship between drawing performance and cerebral metabolism in AD, which cannot be accounted for by overall dementia severity. Differences between the drawing performance of AD and unilateral brain damaged patients are discussed, and further applications of the rating scales (provided in the Appendix) are suggested.