Measurement of disease progression in Alzheimer's disease.

Riege and Metter's comprehensive review deals with many issues pertaining to Alzheimer's disease research. We agree with the authors that early diagnosis and evaluation of disease progression represent key points that must be addressed in an integrated manner. Brain imaging holds great promise for the resolution of both issues.

Differences in lateral hemispheric asymmetries of glucose utilization between early- and late-onset Alzheimer-type dementia.

Positron emission tomography with [18F]fluorodeoxyglucose revealed greater right than left hemispheric impairment of cortical glucose metabolism in patients with probable Alzheimer's disease who were younger than 65 but not in those over 65. This asymmetry was related to poor visuospatial performance.

Memory evaluation in Alzheimer's disease. Caregivers' appraisals and objective testing.

OBJECTIVES: To evaluate if caregivers are reliable informants concerning memory deficits in patients with Alzheimer's disease (AD). DESIGN: Responses of caregivers of patients with probable AD and responses of healthy control subjects on a standardized memory questionnaire were compared with objective measures of cognition (Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery) and with clinical estimates of activities of daily living, depression, and psychopathology (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] clinical assessment battery) using the Self-report Memory Questionnaire. SETTING: A federally funded AD research center. SUBJECTS: The referred sample included 117 patients with probable AD, their informants, and 41 healthy control subjects age-matched to the patients. Patients and control subjects were between the ages of 58 and 85 years, had between 9 and 19 years of education, and were in good health. EXCLUSIONS: Patients who did not meet NINCDS-ADRDA criteria of probable AD. MAIN OUTCOME MEASURE: The optimal number of questionnaire items yielding the best combination of sensitivity and specificity. RESULTS: An abbreviated version of the scale, renamed the Short-Memory Questionnaire, had excellent specificity and sensitivity for identifying dementia. Positive and negative predictive values were 63.5% and near 100%, respectively. The Short-Memory Questionnaire showed good reliability, internal consistency, and external validity. Caregiver appraisals of memory deficits significantly correlated with objective measures of memory and also with generalized cognitive dysfunction. CONCLUSIONS: Caregivers of patients with AD are reliable informants of their relatives' deficits. The Short-Memory Questionnaire is an easily administered, informant-based scale that may be useful in clinical settings or epidemiologic studies to screen out persons with memory difficulties.

Variability in annual Mini-Mental State Examination score in patients with probable Alzheimer disease: a clinical perspective of data from the Consortium to Establish a Registry for Alzheimer's Disease.

OBJECTIVE: To determine the variability in annual Mini-Mental State Examination scores of patients with Alzheimer disease enrolled in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). PATIENTS: A total of 372 patients with probable Alzheimer disease with 1 or more years of follow-up. SETTING: Twenty-one CERAD clinical sites throughout the United States. RESULTS: An average annual decline of 3.4 points in CERAD patients returning for longitudinal reassessments was close to the SD of the measurement error of 2.8 points for the Mini-Mental State Examination. There was wide variability in individual rates of decline. Even with 4 years of follow-up, 15.8% of the patients had no clinically meaningful decline in Mini-Mental State Examination score (defined as a change in initial score >3, ie, 1 SD of measurement error). Validity of measurements of the rate of change in Mini-Mental State Examination scores improved with longer observation intervals and was reliable for most patients when observations were separated by 3 or more years. CONCLUSIONS: Although the Mini-Mental State Examination is a useful screening instrument to assess level of cognitive function, it has limited value in measuring the progression of Alzheimer disease in individual patients for periods less than 3 years because of a large measurement error and substantial variation in change in annual score.

Longitudinal study of cerebral metabolic asymmetries and associated neuropsychological patterns in early dementia of the Alzheimer type.

Regional cerebral metabolic rates for glucose (rCMRglc), as measured with positron emission tomography, and neuropsychological function were studied longitudinally (range, 15 to 48 months) in 11 mildly impaired patients with dementia of the Alzheimer type (DAT) and compared with results from patients with moderate and severe DAT and from controls. At initial evaluation, association cortex metabolic asymmetries were greater in patients with DAT than in controls for all dementia severities and correlated significantly with neuropsychological discrepancies between visuospatial and language abilities in patients with moderate dementia. In mildly impaired patients, right-left metabolic asymmetries in the association cortices were directionally stable and became more pronounced over time. At initial evaluation, these patients had significant impairment, relative to controls, on tests of memory and attention to complex tasks but not on tests of language and visuospatial function. Memory, attention, language, and visuospatial impairments, however, all worsened significantly over time. In mildly impaired patients, correlations between right-left metabolic asymmetries and neuropsychological discrepancies were insignificant initially but were significant at last evaluation. These results demonstrate that heterogeneous nonmemory language and visuospatial impairments in early DAT are related to and predicted by the earlier-appearing distribution of metabolic reductions in the association neocortex.

Olfactory detection and identification performance are dissociated in early Alzheimer's disease.

Ten carefully screened men with very mild symptoms of Alzheimer's disease (AD) and ten healthy controls of similar age were compared on multiple chemosensory tasks: odor detection and identification, and taste detection. The patients scored significantly worse than controls on identification of odors and of a subset of airborne stimuli providing trigeminal stimulation. In contrast, the patients' olfactory detection thresholds as well as taste detection thresholds were not impaired relative to those of controls. The patients' scores on neuropsychological tests and the results 18F-2 deoxy-D-glucose PET studies did not correlate with any of the chemosensory measures. The isolated odor identification deficit suggests that the initial chemosensory impairment in AD is central rather than peripheral.

Longitudinal studies of regional cerebral metabolism in Alzheimer's disease.

Measurement of cerebral glucose metabolism in six patients with Alzheimer's 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.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part XI. Clinical milestones in patients with Alzheimer's disease followed over 3 years.

The rate of cognitive decline, measured by psychometric testing, is widely used to track the progression of Alzheimer's disease (AD). As an alternative approach, we studied clinical measures as markers of the progression of dementia in 343 community-dwelling patients with probable AD enrolled in the multi-center Consortium to Establish a Registry for Alzheimer's Disease (CERAD) project. Subjects received standardized evaluations at entry and at annual follow-up. Decline on the Clinical Dementia Rating, loss of instrumental activities of daily living, failure to recall three words on the Mini-Mental State Examination (MMSE), and decline of the total MMSE score to below 10 were high-risk milestones, with cumulative frequencies exceeding 50% at 3 years. Loss of dressing and toileting activities occurred at intermediate rates, while loss of eating ability was rare. The risk of reaching clinical milestones and the annual rate of cognitive decline on the MMSE were directly correlated. Clinical milestones are useful indices of the progression of dementia in patients with AD.

Clinical and neuropsychological differences between patients with earlier and later onset of Alzheimer's disease: A CERAD analysis, Part XII.

To determine whether the age of the onset of Alzheimer's disease (AD) is related to the expression and rate of decline of this disorder, we examined the clinical and neuropsychological performance of 421 patients entered into the Consortium to Establish a Registry for Alzheimer's Disease and followed annually for up to 4 years. Statistical analyses were based on multivariable logistic regression analysis for dichotomous clinical measures and multivariable linear regression analysis for psychometric measures. All analyses examined the effect of age after controlling for gender, education, and stage of dementia. Clinical information obtained on entry into the study indicated that younger patients performed more poorly on measures of language and concentration, and older patients performed more poorly on measures of memory and orientation. On neuropsychological measures at entry, younger patients, performed more poorly on praxis and had significantly higher scores of confrontation naming. Younger age predicted a significantly faster rate of progression for all neuropsychological measures. These findings support the concept of age-related clinical subtypes of AD.

The consortium to establish a registry for Alzheimer's disease (CERAD). Part IV. Rates of cognitive change in the longitudinal assessment of probable Alzheimer's disease.

Reliable information on rate of progression of cognitive impairment in probable Alzheimer's disease (AD) is important for evaluating possible beneficial effects of therapeutic agents and in planning long-term care for patients with this chronic illness. However, wide variability exists in published rates of change for psychometric measures of the dementing process, and there is need for an accurate analysis of large numbers of persons with the disorder studied over long periods. Utilizing the large, well-characterized sample of the Consortium to Establish a Registry for Alzheimer's Disease and employing a least squares regression method to adjust for different levels of impairment and periods of observation, we report rates of change on the Short Blessed Test, Mini-Mental State Examination, Blessed Dementia Scale, Clinical Dementia Rating, and other cognitive measures in 430 patients with probable AD (mean age at entry = 70.9 +/- 8.0 SD years) studied for up to 4 years. We found that rate-of-change determinations are less reliable when the observation period is 1 year or less, that dementia progression may be nonlinear when described by certain measures, and that simple change scores do not accurately characterize the rate of decline. We also found that rate of progression in AD is determined by the severity of cognitive impairment: the less severe the dementia, the slower the rate of decline.

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.

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 Alzheimer's 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.

Concomitants of visual hallucinations in Alzheimer's disease.

Visual hallucinations (VH) are the most common hallucinations in Alzheimer's disease (AD), but their relationships with other behavioral symptoms and measures of cognitive performance are unclear. Using the BE-HAVE/AD, a semistructured behavioral inventory, we identified 20/160 AD patients (13%) who were currently having VH. Patients with VH performed worse on the Mini-Mental State Examination and had more behavioral symptoms than patients without VH. Symptoms particularly associated with VH included auditory hallucinations, verbal outbursts, delusions, and paranoid ideation. Principal factor analysis of the BEHAVE/AD yielded four factors accounting for 47% of the total variance. VH loaded on two factors involving symptoms of "paranoia" and "agitation/hallucinations." Our findings suggest that VH in AD patients are common, often occur in the presence of specific behavioral disturbances, and may have management implications.

Assessment of agitation in Alzheimer's disease: the agitated behavior in dementia scale. Alzheimer's Disease Cooperative Study.

OBJECTIVES: To develop and evaluate the psychometric properties of a new measure of agitation, the Agitated Behavior in Dementia scale (ABID). The ABID consists of 16 items designed specifically to evaluate frequency of and caregiver reaction to common agitated behaviors in community-residing dementia patients. DESIGN: The ABID was administered at the baseline assessment of a multi-site controlled treatment study to reduce agitation in Alzheimer's Disease (AD). Reliability was assessed by evaluating internal consistency and test-retest correlations. Validity was assessed by examining correlations with other constructs, including demographics, cognitive status, and overall behavioral disturbance. SETTING: Twenty-one sites across the US, comprising the Alzheimer's Disease Cooperative Study, contributed subjects to the investigation. PARTICIPANTS: A total of 148 community-residing AD patients, living with a spouse or adult relative who acted as an informant. Mean age was 75 years, and mean Mini-Mental State Exam (MMSE) score was 13. MEASUREMENTS: Cognitive status was assessed using the MMSE. Behavioral disturbance was assessed using the Behavior Rating Scale for Dementia of the Consortium to Establish a Registry for Alzheimer's Disease, the Revised Memory and Behavior Problems Checklist, and the Cohen-Mansfield Agitation Inventory. RESULTS: Reliability of the ABID was excellent, with internal consistency of 0.70 and test-retest reliability of 0.60 to 0.73. Validity was confirmed by correlations with related measures and lack of correlation with unrelated constructs. CONCLUSIONS: The ABID is brief, easy to administer, and provides objectively anchored observations of problems. It is a promising measure for studies of community-residing AD patients.

On the use of surrogate respondents for controls in a case-control study of Alzheimer's disease.

OBJECTIVE: To examine the presence and extent of bias introduced by using surrogate respondents for healthy controls in a case-control study of Alzheimer's disease (AD). DESIGN: Comparative study of matched responses to questionnaire ascertaining lifestyle issues. SETTING: University Hospitals/Case Western Reserve University Alzheimer Center. PARTICIPANTS: Controls (n = 50) were identified through the Research Registry. Surrogates (n = 50) were their healthy relatives or friends. MEASUREMENTS: Answers in the areas of demographic and occupational history, smoking habits, medical history, dietary intake, and leisure and work activities were recorded. The analysis was based on methods for paired data. Continuous variables were analyzed, focusing on paired differences between self and surrogate responses. RESULTS: For occupations and exposures, over 80% of the surrogates agreed with the subjects on over 80% of the questions. On smoking history, over 90% of the surrogates agreed with the subjects on over 70% of the questions. On leisure and work activities, over 70% of the surrogates agreed with the subjects on over 50% of the questions. There was less agreement regarding medical history. For continuous variables, most paired t-tests of zero mean difference between self and surrogate responses resulted in nonrejection of this hypothesis. Computed mean differences were not always positive or always negative. CONCLUSION: We did not find systematic under- or overreporting by the surrogates of the controls. Therefore, if there are biases in the responses of surrogates of the AD cases in our case-control study, they would not be canceled out by using surrogates for the controls.

A comparison of the Cohen-Mansfield agitation inventory with the CERAD behavioral rating scale for dementia in community-dwelling persons with Alzheimer's disease.

In a group of 242 community-dwelling patients with Alzheimer's disease (AD), a longitudinal comparison was made of two caregiver-administered instruments for assessment of behavioral disturbance; the Cohen-Mansfield Agitation Inventory (CMAI) and the CERAD Behavioral Rating Scale for Dementia (BRSD). We examined records of the 206 patients with baseline and 12-month follow-up data for the CMAI and the BRSD who also had tests of cognitive (Mini-mental State; MMSE) and global function (Clinical Dementia Rating; CDR and Functional Assessment Staging; FAST). Among 114 AD subjects, the correlation between total CMAI at baseline and 1 month readministration was 0.83 (p < 0.0001). In the same subjects, stratified into 5 groups by MMSE scores, the correlations between BRSD baseline and 1-month scores ranged from 0.70-0.89 (p < 0.0001). There was high correlation between total scores of both instruments at baseline and 12 months. In addition, all CMAI subscales except Verbally Aggressive correlated significantly with total BRSD score at both time points. At baseline, BRSD subscales for irritability/aggression, behavioral dysregulation and psychotic symptoms and at 12 months, irritability/aggression and behavioral dysregulation correlated with total CMAI scores. Neither scale changed significantly over 1 year, but there was wide individual variation. CMAI and BRSD scores correlated with 1-year change in the FAST, but not with MMSE or CDR (which weighs cognition heavily), suggesting that behavioral disturbance may be more strongly related to ability to manage activities of daily living (executive function) than to other aspects of cognition. The CMAI and BRSD appear to be interchangeable as measures of agitation, with the CMAI possibly more useful for patients who lack language and the BRSD more sensitive to apathy and depression.

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 Alzheimer's 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 Alzheimer's disease.

Evaluation of risk factors for Alzheimer's disease in elderly east Africans.

A number of biological risk factors have been implicated for Alzheimer's disease (AD). The investigation of prevalence rates of AD in crosscultural populations has much potential in validating these factors. We previously assessed brain amyloid beta (A beta) protein deposition and other lesions associated with AD as possible markers for preclinical AD in elderly nondemented East Africans. In further analysis, we demonstrate that 17-19% of elderly East African subjects without clinical neurological disease exhibited neocortical A beta deposits and minimal neurofibrillary changes at necropsy that was qualitatively and quantitatively similar to that in an age-matched elderly control sample from Cleveland, OH. A beta deposits varied from numerous diffuse to highly localized neuritic plaques and were predominantly reactive for the longer A beta 42 species. In parallel studies, we evaluated another recently implicated factor in AD, the apolipoprotein E genotype. We found relatively high frequencies of the apolipoprotein E-epsilon 4 allele in elderly nondemented East Africans. The frequencies were comparable to those in other African populations but higher than in subjects from developed countries. Our limited study suggests that elderly East Africans acquire cerebral lesions found in AD subjects but the apolipoprotein E-epsilon 4 allele may not be a highly specific factor for the disease among East Africans.

Growth of rat mesangial cells on oxidized extracellular matrix increases inducible nitric oxide synthase activity.

Biochemical modification of extracellular matrix (ECM) proteins can alter the function in overlying cells. We tested the hypothesis that metal-catalyzed oxidation of native ECM and individual matrix proteins modulates the activity of inducible nitric oxide synthase (iNOS) in cultured rat mesangial cells (RMC). Oxidized modification of native ECM resulted in a 32% increase in iNOS activity (P<0.01) without influencing the response to supplemental L-arginine or to the addition of the iNOS inhibitor, L-NAME. Immunoblot analysis indicated that enhanced iNOS activity was not associated with a parallel rise in the cytosolic content of iNOS. Synthesis of type IV collagen was unaffected by growth of RMC on oxidized native ECM. Oxidation of three normal constituents of the mesangial matrix - type IV collagen, laminin, and fibronectin - also stimulated iNOS activity in overlying RMC by 18-32% (P<0.05). Growth of RMC on oxidized type I collagen or Vitrogel had no effect on NO production. We conclude that oxidized modification of the mesangial matrix promotes increased iNOS activity and NO production by mesangial cells. Further work is required to determine whether this response limits glomerular injury or promotes damage to the mesangium in oxygen free radical-mediated diseases such as chronic renal failure, atherosclerosis and diabetes.

The factor structure of the Brief Psychiatric Rating Scale in Alzheimer's disease.

The factor structure of the Brief Psychiatric Rating Scale (BPRS) is well established with young psychiatric patients. A study by Overall and Beller showed, however, that its factor structure was different with geropsychiatric patients. Although the BPRS has been used in assessing the behavioral characteristics of patients with probable Alzheimer's disease (AD), its factor structure has not been established with these patients. The present study investigated the factor structure of the BPRS among patients with clinically diagnosed AD by (NINCDS/ADRDA) criteria. The scale had limited usefulness with outpatients with mild AD. The factor structure obtained was similar to that found with other patient groups, but a unique factor, including the items Tension and Uncooperativeness, probably reflects the behavioral and psychological agitation characteristic of some AD patients. We recommend caution be taken in generalizing data from younger psychiatric samples to older adult patients with dementia.