Comparison of Lewy body variant of Alzheimer's disease with pure Alzheimer's disease: Consortium to Establish a Registry for Alzheimer's Disease, Part XIX.

OBJECTIVE: To compare the clinical, neuropsychological, and neuropathologic findings in patients with AD alone with those in patients with the Lewy body variant of AD (LBV). BACKGROUND: Prior studies indicate that patients with LBV not only have distinct clinical and neuropsychological differences from those with AD alone, but have a poorer prognosis with shorter survival time. METHODS: The authors evaluated 74 patients with autopsy-confirmed AD alone and 27 patients with LBV, and compared demographic characteristics and clinical, neuropsychological, and neuropathologic findings. RESULTS: The two groups of patients were equivalent with respect to age at time of entry into the study, years of education, and sex. Two or more extrapyramidal clinical manifestations were found in 44% of patients with LBV, compared with 16% of patients with AD alone (p = 0.02). Duration of survival after entry into the study was similar in both groups, with a mean survival of 3.6 (+/-2.1) years for AD alone versus 3.8 (+/-1.9) years for LBV. Of the various neuropsychological tests administered at the last Consortium to Establish a Registry for Alzheimer's Disease evaluation, only delayed recall of a learned word list was significantly different in the two groups, with 32% of patients with LBV versus 15% of patients with AD alone recalling any items (p = 0.04). Neuropathologic findings confirmed those of previous studies and showed that neurofibrillary tangles were significantly less frequent in the neocortex of patients with LBV than in those with AD alone. CONCLUSION: Compared with patients with AD alone, those with LBV had a greater frequency of extrapyramidal manifestations, somewhat better recall on a selected memory task at their final evaluation, and a significantly lower frequency of neocortical neurofibrillary tangles at autopsy. There were no differences between the two groups, however, in survival time from entry into the study.     

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer's disease

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed brief, comprehensive, and reliable batteries of clinical and neuropsychological tests for assessment of patients with the clinical diagnosis of Alzheimer's disease (AD). We administered these batteries in a standardized manner to more than 350 subjects with a diagnosis of AD and 275 control subjects who were enrolled in a nationwide registry by a consortium of 16 university medical centers. The tests selected for this study measured the primary cognitive manifestations of AD across a range of severity of the disorder, and discriminated between normal subjects and those with mild and moderate dementia. The batteries also detected deterioration of language, memory, praxis, and general intellectual status in subjects returning for reassessment 1 year later. Interrater and test-retest reliabilities were substantial. Long-term observations of this cohort are in progress in an effort to validate the clinical and neuropsychological assessments and to confirm the diagnosis by postmortem examinations. Although information on validation is limited thus far, the CERAD batteries appear to fill a need for a standardized, easily administered, and reliable instrument for evaluating persons with AD in multicenter research studies as well as in clinical practice.     

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease

The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as "definite Alzheimer's disease" (AD), "probable AD," "possible AD," and "normal brain" to indicate levels of diagnostic certainty, reduce subjective interpretation, and assure common language. To pretest the protocol, neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied, the CERAD neuropathology protocol will help to refine diagnostic criteria, assess overlapping pathology, and lead to a better understanding of early subclinical changes of AD and normal aging.     

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part III. Reliability of a standardized MRI evaluation of Alzheimer's disease.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed procedures for standardized imaging and reporting of magnetic resonance (MR) findings in Alzheimer's disease (AD) for use by neuroradiologists in multiple medical centers using a variety of MR equipment and field strengths. After initial pretesting, we revised the protocol, expanded the summary rating scale to seven points, and added more illustrations. Fourteen participating neuroradiologists evaluated 28 MR scans of elderly patients, giving us the basis for judging interrater agreement. We obtained acceptable intraclass correlations (greater than 0.79) for rating the size of the lateral and third ventricles and the temporal horn. Less satisfactory intraclass correlations occurred when rating other areas, including (1) global atrophy of the brain (0.70); (2) dilatation of the sulci of the temporal lobe (0.66); (3) frequency, location, and severity of white matter lesions (0.77); (4) sylvian fissure enlargement (0.70); and (5) cerebral sulcal dilatation (0.64). We also saw considerable variation in the reporting of cortical and lacunar infarcts. Despite careful design of the rating methodology and readings by experienced neuroradiologists, we did not find satisfactory interrater agreement for interpreting MR findings in elderly subjects. These findings may explain the difficulties encountered in applying similar subjective rating techniques that meet with success at one institution to multicenter studies. More objective and reproducible procedures are needed for interpretation of neuroimaging findings of AD in multicenter studies.     

Consortium to Establish a Registry for Alzheimer’s Disease (CERAD): The first twenty years

The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) was funded by the National Institute on Aging in 1986 to develop standardized, validated measures for the assessment of Alzheimer’s disease (AD). The present report describes the measures that CERAD developed during its first decade and their continued use in their original and translated forms. These measures include clinical, neuropsychological, neuropathologic, and behavioral assessments of AD and also assessment of family history and parkinsonism in AD. An approach to evaluating neuroimages did not meet the standards desired. Further evaluations that could not be completed because of lack of funding (but where some materials are available) include evaluation of very severe AD and of service use and need by patient and caregiver. The information that was developed in the U.S. and abroad permits standardized assessment of AD in clinical practice, facilitates epidemiologic studies, and provides information valuable for individual and public health planning. CERAD materials and data remain available for those wishing to use them.     

Detection and staging of dementia in Alzheimer's disease. Use of the neuropsychological measures developed for the Consortium to Establish a Registry for Alzheimer's Disease.

Our earlier studies using the Consortium to Establish a Registry of Alzheimer's Disease neuropsychological battery showed that delayed recall was a highly sensitive indicator of early Alzheimer's disease. None of the learning and memory measures in the battery were found to be useful in staging the severity of this form of dementia. This study explores the nonmemory functions (fluency, naming, and praxis) of the Consortium to Establish a Registry of Alzheimer's Disease battery and asks whether performance on any of these measures adds to the detection of early Alzheimer's disease or is sensitive to the later progression of the illness. We stratified patients with this disease according to severity (mild, moderate, severe), and compared them with age-, education-, and gender-matched control subjects (group N = 49 each). Multivariate procedures and cutting scores were used to determine the efficacy of the various measures in distinguishing between the cases and control subjects. Impairment of delayed recall was again found to be the best discriminator for detecting mild cases of Alzheimer's disease. Confrontation naming was the only nonmemory factor that assisted in this discrimination. For staging the illness, a combination of measures including fluency, praxis, and recognition memory best differentiated cases with mild dementia from those with either moderate or severe stages of disease. Measures of delayed recall quickly "bottomed out" in the patients with Alzheimer's disease and proved of little value in staging the disorder.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Severe Mini-Mental State Examination: a new neuropsychologic instrument for the bedside assessment of severely impaired patients with Alzheimer disease

The bedside and office assessment of cognitive abilities in moderately to severely impaired patients with Alzheimer disease could be enhanced by a well-standardized instrument. The authors' group has developed such an instrument (i.e., Severe Mini-Mental State Examination; SMMSE) to assess this population. Based on the Folstein Mini-Mental State Examination (MMSE), the SMMSE, which totals 30 points, was designed to briefly assess cognitive domains relatively preserved in moderate to severe Alzheimer disease. One hundred eighty-two patients with possible or probable Alzheimer disease were administered both the MMSE and SMMSE. Performances on the SMMSE and MMSE were found to correlate significantly only when MMSE fell below 9 points (p < 0.0001). However, as performance on the MMSE approached floor levels, patients continued to score at half maximal levels on the SMMSE. Functional staging with the Clinical Dementia Rating Scale and the Global Deterioration Scale also were found to significantly correlate with performance on the SMMSE (p < 0.001). Test-retest performance on both the SMMSE and MMSE was relatively stable over a period of 5 months. Inter-rater reliability of the SMMSE was excellent. These results suggest that the SMMSE has both construct and criterion validity for assessing severely impaired Alzheimer disease patients. Our results also suggest that the SMMSE may be a useful instrument for assessing severely impaired patients at the bedside and in the office.     

Mini-Mental State Examination and Mattis Dementia Rating Scale performance differs in Hispanic and non-Hispanic Alzheimer's disease patients.

Little information exists regarding the performance of Spanish-speaking versus English-speaking patients with Alzheimer's disease (AD) on the Mini-Mental State Examination and the Mattis Dementia Rating Scale. In an attempt to identify culturally biased MMSE items or DRS subscales, we matched Spanish-speaking Hispanic and English-speaking non-Hispanic White community-dwelling AD patients by their MMSE scores and examined specific items within each scale. Our findings indicate that Hispanic AD patients perform significantly worse than non-Hispanics in terms of total DRS score, scores on the DRS subscales for Conceptualization and Memory, and on serial subtraction (or backward spelling item) of the MMSE. While mildly to moderately demented Hispanic and non-Hispanic patients obtained comparable scores on the DRS, severely impaired Spanish-speaking participants obtained considerably lower DRS scores than their English-speaking counterparts. The discrepancy in the DRS scores of the severely impaired Hispanic and non-Hispanic examinees might reflect a cultural bias in the test or educational differences between the groups. Alternatively, the DRS may be more sensitive than the MMSE for detecting severe cognitive impairment in Hispanic patients.     

Sylvian fissure size in schizophrenia measured with the magnetic resonance imaging rating protocol of the Consortium to Establish a Registry for Alzheimer's Disease.

OBJECTIVE: Since previous work indicated smaller than normal temporal lobe structures in schizophrenic patients, the authors tested the hypothesis that this abnormality might be reflected in abnormally large sylvian fissures. METHOD: The subjects were 48 schizophrenic patients and 51 normal comparison subjects matched groupwise with regard to age and sex. CSF spaces (sylvian fissures, temporal lobe sulci, temporal horns, third ventricle, lateral ventricles, and superficial cerebral sulci) were visually assessed with the magnetic resonance imaging rating protocol of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). RESULTS: The sylvian fissures of the schizophrenic patients were found to be bilaterally wider than those of the comparison subjects. There were no other significant differences. CONCLUSIONS: Schizophrenic patients appear to have larger than normal sylvian fissures, which may reflect smaller superior temporal gyri.     

Levels of estrogen receptors alpha and beta in frontal cortex of patients with Alzheimer's disease: relationship to Mini-Mental State Examination scores

Estrogen exerts beneficial effects on the brain throughout life. Studies demonstrate that estrogen is neuroprotective and that reduced brain estrogen activity may influence the clinical course of Alzheimer's disease (AD). Changes in levels of estrogen receptors have been detected in postmortem brain tissue of AD patients. Very little is known about the relationship between clinical stage and levels of estrogen receptors in postmortem brain. We hypothesized that estrogen receptor levels would be related to severity of cognitive impairment assessed proximate to death. Western blotting was used to quantify ER-alpha and ER-beta in nuclear, cytosolic, and crude membrane fractions of superior frontal cortex from 25 AD patients. Multiple linear regression analyses adjusted for age, sex, and education showed a significant linear relationship between Mini-Mental State Examination score (MMSE) and wild-type nuclear ER-alpha (a = 5.463, p = 0.03), but none between MMSE and wild-type nuclear ER-beta (a = 2.29, p = 0.36). We incidentally observed additional higher and lower molecular mass bands for ER-alpha in study subjects. Additional experiments performed on frontal cortex nuclear fractions prepared from subjects enrolled in a different study confirmed that these same bands are present in female and males with and without AD. Together our data show a relationship between wild-type ER-alpha and level of cognitive impairment in AD, and also suggest the possibility that variant isoforms of ER-alpha may be present in frontal cortex of patients with and without AD.     

Discriminant validity of a reduced set of Mini-Mental State Examination items for dementia and Alzheimer's disease.

Linear discriminant analysis was used to construct a series of discriminant functions including subsets of demographic variables and Mini-Mental State Examination item responses for a case series and a population sample. A 9-item discriminant function including the variables for time orientation, recall, calculation, copying a figure, age, writing, 3-step command, naming, and race distinguished demented subjects from community controls with 91% sensitivity and 88% specificity. The same discriminant function classified Alzheimer's disease patients and controls with 96% sensitivity and 98% specificity. This discriminant function has been cross-validated as a potential screening instrument for Alzheimer's disease in a community-based sample.     

Suicide in two patients with a diagnosis of probable Alzheimer disease.

Two patients meeting the criteria for probable Alzheimer disease (AD) who were participating in a phase 3 clinical program with eptastigmine, a cholinesterase inhibitor, committed suicide. The first patient committed suicide by a self-inflicted gunshot wound to the head. The second patient committed suicide by jumping from a 19th story window. These two patients shared several clinical features with those found in the literature: being at the early stages of the disease, having a high level education, with preserved insight, having access to firearms, and being aware of not responding to pharmacological treatment.     

First clinical evaluation of ganstigmine in patients with probable Alzheimer's disease

The objective of this study was to evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics of five fixed doses of ganstigmine (CHF 2819) in patients with probable Alzheimer's disease (AD). This randomized, double-blind, placebo-controlled trial evaluated five dose levels (5, 7.5, 10, 12.5, and 15 mg) administered orally once daily for 7 days. Adverse events and continuous telemetry were collected on successive panels of six patients (five active, one placebo). Acetylcholinesterase, butyrylcholinesterase, and plasma drug levels were measured. A total of 29 patients were randomized and 18 completed the study. A total of seven patients, including five of five in the 12.5-mg panel, discontinued because of adverse events. Four patients were withdrawn administratively from the first panel while an episode of atrial fibrillation (the only serious adverse event) was investigated. This panel was then repeated. Mild, transient headache or nausea were the most commonly reported adverse events. Multiple moderate adverse events in the 12.5-mg panel (including nausea, vomiting, and anorexia) led to the decision not to proceed with a 15-mg panel. Ten milligrams was determined to be the maximum tolerated dose. Ganstigmine exhibited nonlinear pharmacokinetics, was absorbed rapidly, and reached peak concentrations within 1 hour. Acetylcholinesterase inhibition was dose dependent and lasted as long as 24 hours. Ganstigmine, a novel cholinesterase inhibitor, was well tolerated within a dosing range of 5 to 10 mg. Once-daily dosing is supported by data on acetylcholinesterase inhibition.     

Neuropathological findings in patients with clinical diagnoses of probable Alzheimer's disease

To assess prospectively the accuracy of standard antemortem clinical diagnostic criteria for Alzheimer's disease, post-mortem examinations were performed on 25 patients who had met DSM-III criteria for primary degenerative dementia and National Institute of Neurological and Communicative Disorders and Stroke criteria for probable Alzheimer's disease. Seventeen patients (68%) met neuropathological criteria for Alzheimer's disease. Two presenile-onset patients had diffuse neocortical senile plaques of insufficient number for definite Alzheimer's disease. Six patients had non-Alzheimer's disease diagnoses. Five of these six had presenile-onset dementia. These results suggest caution in the antemortem diagnosis of Alzheimer's disease in presenile-onset dementia.     

Relationship between both IQ and Mini-Mental State Examination and the regional cerebral glucose metabolism in clinically diagnosed Alzheimer's disease: a PET study

In order to clarify the hypofunction in which brain areas demonstrate a decline in Intelligence Quotient (IQ), we examined correlations between the IQ and Mini-Mental State Examination (MMSE) and regional cerebral metabolic rate of glucose (rCMRglc) measured using positron emission tomography (PET) in 26 patients with clinically diagnosed Alzheimer's disease (AD). The MMSE scores and full-scale IQ (FSIQ) showed significant correlations with the rCMRglc in the temporal and parietal lobes on both sides and in the left frontal lobe, which were significantly reduced in comparison to those in the normal controls. A multiple regression analysis showed only the MMSE score to predict verbal IQ (VIQ), performance IQ (PIQ) and FSIQ. VIQ was also predicted by the rCMRglc in the left parietal lobe, while PIQ was predicted by the age at onset. The results suggested MMSE to be an index of dementia severity reflected by general intelligence as shown by IQ in AD, and a reduction in the VIQ can thus be used as an index of the left parietal dysfunction, which is not expressed by MMSE.     

Cranial electrostimulation (CES) in patients with probable Alzheimer's disease.

In one study, behavioral disorders of patients with vascular dementia reacted positively to cranial electrostimulation (CES). In the present study, it was examined whether CES could improve cognition and (affective) behavior in patients with probable Alzheimer's disease (AD). Eighteen AD patients, divided into an experimental and a placebo group, were treated for 30 min per day, 5 days a week, for 6 weeks. No improvements in cognition and (affective) behavior were found after CES.     

Mild cognitive impairment is common in Parkinson's disease patients with normal Mini-Mental State Examination (MMSE) scores

PurposeCognitive impairment occurs in the majority of Parkinson's disease (PD) patients, but little is known about detection of mild cognitive impairment (MCI) in this population. We report on the frequency and characteristics of cognitive deficits in PD patients with intact global cognition based on Mini-Mental State Examination (MMSE) performance.MethodsOne hundred and six PD patients with normal age- and education-adjusted MMSE scores (mean [SD] score = 29.1 [1.1]) were administered standardized neuropsychological tests assessing memory, executive function, and attention. Impairment on a cognitive domain was a low score (i.e., ≥1.5 SD below the published normative mean) on at least two measures or tests (for memory and executive abilities) or a single measure (for attention).ResultsMild cognitive impairment was found in 29.2% of PD patients, with 17.9% demonstrating single domain and 11.3% multiple domain impairment. Memory and attention impairment were most common (15.1% and 17.0%, respectively), followed by executive impairment (8.5%). Depending on the measure of disease severity chosen, increasing age and disease severity, anti-anxiety medication use, and a suggestion for increasing severity of daytime sleepiness were independent predictors of cognitive impairment.ConclusionsCognitive deficits are common in PD patients with “normal” cognition based on MMSE performance, suggesting that MCI is under-recognized in clinical practice due to routine use of insensitive screening instruments. In contrast with some previous reports, early memory impairment may be as common as either executive or attentional deficits in PD. In addition, psychiatric medication use and daytime sleepiness may be reversible or treatable contributors to cognitive impairment.